provisional classification and in silico study of ... · provisional classification and in silico...

SI1

SUPPORTING INFORMATION (Nº1)

Provisional Classification and in silico Study of Biopharmaceutical System based on

Caco-2 cell Permeability and Dose number

Hai Pham-The†, Teresa M. Garrigues

§, Marival Bermejo

‡, Isabel González Álvarez

‡, Maikel Cruz

Monteagudo∇,∥,⊥, and Miguel Ángel Cabrera-Pérez*

,†,§,‡

†Molecular Simulation & Drug Design Group. Centre of Chemical Bioactive. Central University of Las Villas.

Santa Clara 54830, Villa Clara, Cuba; §Department of Pharmacy and Pharmaceutical Technology, University

of Valencia, Burjassot 46100, Valencia, Spain; ‡Department of Engineering, Area of Pharmacy and

Pharmaceutical Technology, Miguel Hernández University, 03550 Sant Joan d'Alacant, Alicante, Spain; ∇CIQ, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal; ∥REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal; ⊥Applied Chemistry Research Center (CEQA), Faculty of Chemistry and Pharmacy, Central University of Las Villas. Santa Clara, 54830, Cuba

*To whom correspondence should be addressed: Molecular Simulation & Drug Design Group. Centre of Chemical Bioactive. Central University of Las Villas. Santa Clara 54830, Villa Clara, Cuba. E-mail: [email protected]; [email protected]; [email protected] Phone/fax: 53-42-281192 / 53-42-281130

SI2

Table SI1. Oral Immediate-Release (IR) drugs for Provisional Biopharmaceutical Classification (PBC) based on Caco-2 cell Permeability and revised

aqueous solubility

Drugb WHO

BCS1

BCS

in 2, 3

BCS

in 4

BCS

in 5

BDDCS

in 6

PBC LogPapp

( AB)

LogPapp

(BA)

Fac

%

Fa Ref. Dmin

mg

Dmax

mg

Smina

mg/ml

Smaxa

mg/ml

Therapeutic

category

Acebutolol7-17 I III -5.73±0.5 -5.20 82±9 18-21 200 400 200 fs Antihypertensive

Aceclofenac22, 23 II -4.41 100 200 0.03 vss NSAID

Aspirin8-12, 14, 24-27 I III III III I I -4.60±0.6 -4.69 92±9 15, 19, 28, 29 100 500 5.3 7.3 NSAID

Acrivastine14, 15 III III -5.72 88 15, 19, 21, 28, 29 - 8 0.7 ss Antihistaminic

Acyclovir7-10, 12, 13, 15, 30-36 III III III III IV III -5.99±0.5 25±6 15, 20, 21, 37-39 200* 800 1.8 504.5 Antiviral

Albendazole40 II/IV II II IV -5.18 -5.49 20 38, 41, 42 200 400 pi - Antibacterial

Alprazolam13, 43, 44 I I I -4.59±0.4 -4.64 92±3 19-21, 37 0.25 2 0.07 0.11 Anxiolitic

Alprenolol8, 9, 12-15, 32, 44-49 I I -4.09±0.6 96±3 18-21, 28, 29, 32,

45, 50

100 200 50 - Antihypertensive

Amantadine51 III I -4.65 90±4 19, 20, 51 - 100 6.29 50 Antiviral

Ambroxol52 I I I -4.35 High (d) 15 30 10.9 20 Expectorant

Amiloride9, 11, 13, 35, 47, 51-54 I III I I/III III III -5.37±0.5 -5.27 50 21, 39, 51 - 5 50 659 Antihypertensive

Alminoprofen22, 23 II -4.34 - 300 0.31 - Antiinflamatory

Aminopyrine7-10, 12, 22, 46, 55 I I -4.34±0.2 100 19, 21 - 300 53 55.6 Analgesic

Amisulpride55 IV IV -5.66 95 19, 20 100 200 pi 0.54 Antipsychotic

Amitriptyline27, 35 I I I/II I I I -4.26 95 19, 20, 37 10 150 9.7 fs Antidepressant

Amoxicillin9, 10, 14, 15, 35, 56 I III I III III III -6.29±0.7 95±3 15, 20, 28, 29, 37 125 875 4 - Antibacterial

Amphetamine9, 16, 57, 58 III I -4.39 -4.67 90 19, 21 10 30 30 fs CNS stimulant

Ampicillin45, 54, 59, 60 III III -6.07±0.6 60±13 19, 20, 45, 54 250 500 12 13.9 Antibacterial

Amprenavir16, 17, 61, 62 II IV -4.98±0.3 -4.58 70 17, 63 - 50 0.042 - Antiviral

Antipyrine9, 11, 13-15, 32, 45, 47,

54, 56, 64, 65

I/III I I I -4.33±0.5 98±2 15, 19-21, 37 250 500 56.12 670 Analgesic

Artesunate9, 55, 66-68 II/IV IV -5.40 Rapid (d) - 50 0.1 vss Antimalary

Astemizole69 II III -5.15 -5.41 100 19 - 10 0.125 3.115 Antihistaminic

Atenolol7-17, 26, 30, 33, 40, 45-

47, 64, 70-75

III III III III III III -5.68±0.5 -5.85 53±9 15, 18-20, 28, 29,

37, 39, 76

50 100 24.8 26.5 Antihypertensive

Atorvastatin58, 77 II II II IV -5.31 -4.45 34±6 10 80 0.02 - Anticholesterol

Atropine13, 35 III I/III I/III III I -4.70±0.01 94 19, 20 - 1 2.2 465.9 Antispasmodic

Azithromycin8, 9, 13, 15, 24 II/IV II II III IV -6.25 60 15, 20, 78 200 600 ss 39 Antibacterial

Baclofen79 III III -6.05 95 19, (d) 10 20 2.1 4.55 Anticonvulsant

Benazepril13 I I III -6.89 37 76 5 40 78 >100 Antihypertensive

Bendroflumethiazide51 III III -5.88 100 19, 20, 51 5 10 0.108 0.159 Antihypertensive

Betaxolol8, 9, 13, 15, 66 I I -4.27 90 19-21, 28, 29, 51 10 20 0.451 69 Antihypertensive

Bicalutamide80 II II II -4.66 -3.92 90 19 - 50 0.005 - Antineoplastic

*This dose value was applied (as recommended in WHO EML)1

SI3

Table SI1. (Continued)

Drugb WHO

BCS1

BCS

in 2, 3

BCS

in 4

BCS

in 5

BDDCS

in 6

PBC LogPapp

( AB)

LogPapp

(BA)

Fac

%

Fa Ref. Dmin

mg

Dmax

mg

Smina

mg/ml

Smaxa

mg/ml

Therapeutic

category

Bisoprolol81 I III I -4.76 90 19, 20, 37 5 10 2.24 - Antihypertensive

Bosentan9, 82 II IV -5.98±0.01 56 37 62.5 125 pi 500 Antihypertensive

Bromazepam16 I I -4.40 -4.68 84 19, 21, 28, 29 1.5 6 0.17 0.6 Anxiolitic

Bromocriptine55, 65 I IV -5.77±0.2 31±3 19, 37, 63, 83 2.5 5 0.002 0.8 Antivonvulsant

Brompheniramine54 I -4.66 100 19 - 6 fs 200 Antihistaminic

Budesonide55 I I -4.79 100 19, 20 - 3 0.016 0.022 Antiasthmatic

Bupropion9, 14, 15, 17, 22, 55, 58 I I I -4.08±0.3 -4.67 87 15, 19, 28,29 75 100 312 - Antidepressant

Buspirone43 I I II II -4.59 -4.55 100 19, 37 5 10 0.021 0.38 Anxiolitic

Caffeine7, 8, 13, 15, 25-27, 31, 44, 46, 54,

56, 69, 84

I/III I I I -4.35±0.3 -4.41 100 15, 19, 20, 28, 29, 37

65 500 37.07 37.48 Wide therapeutic

index

Camazepam16, 17 I -4.46 -4.77 100 19, 21 - 30 ss 1 Anxiolitic

Captopril85 III III I/III III III -4.82 74±7 29, 51, (d) 25 100 100 160 Antihypertensive

Carbamazepine16, 27, 31, 70, 86 II II II II II II -4.44±0.2 -4.51 100 19, 51, 39 200 300 0.44 - Anticonvulsant

Carisoprodol51 II -4.66 250 350 0.3 0.48 Anticonvulsant

Cefatrizine14 IV -6.12 76 15, 20, 28,29 - 500 ss 2.505 Antibiotic

Ceftibuten45 IV IV -6.34±0.9 70 87, (d) - 400 0.08 0.1 Antibiotic

Cefuroxime14, 16, 65 IV III III -6.29±0.1 -6.40 5 20, 28, 29 125 500 200 - Antibiotic

Celecoxib26 II II II -4.75 -4.82 Good 88 100 200 0.003 0.007 Antiinflamatory

Celiprolol89, 90 III III -6.48 -5.68 50 19, (d) - 200 151 176 Antihypertensive

Cephalexin9, 14-16, 45, 91-93 III III -4.94±1 -4.95 96±4 15, 20, 37 500 750 12.5 - Antibiotic

Cephradine94, 95 III III -5.54±0.2 96±3 19, 21, 96 - 500 21.3 26 Antibiotic

Cetirizine16, 17 I III III III -5.50±0.2 -4.87 86±14 37, 63, 81,

97, 98

- 10 0.101 - Antihistaminic

Chloramphenicol8-11, 16, 66, 82, 92, 93 III III III I I -4.52±0.3 -4.93 90 15, 19-21, 29 100 250 4 4.427 Antibacterial

Chloroquine69 I I I I III I -4.55 -4.35 100 19, 20 250 500 100 - Antiinflamatory,

antimalarial

Chlorothiazide7-10, 12-16, 66, 92, 93, 99,

100

IV IV IV IV -5.93±0.7 -5.56 24±21 15, 21, 28, 29, 39

250 500 1.08 - Diuretic

Chlorpheniramine101, 102 I I/III I I I -4.28 74±16 19, 20, 37, 98 2 4 5.5 160 Antihistaminic

Chlorpromazine7-9, 12, 46, 53, 69 III I II/IV II I I -4.75±0.3 -4.92 95±5 19, 20, 37 100 200 400 - Antipsychotic

Chlorprothixene51 I -4.74 100 37, 51 10 100 s 100 Antipsychotic

Chlortetracycline59 III -6.32 60 103 - 10 0.75 1.1 Antibacterial

Chlorzoxazone51 II II -4.19 90 19, 51 250 500 0.25 1.208 Anticonvulsant

Cimetidine7-16, 30, 47, 53, 69, 84, 104 III III III III III -5.80±0.3 -5.37 76

±

12

12, 15, 16, 19-21,

24, 25, 28, 29, 32,

37, 39, 100, 105

200 800 18.91 - Antiulcerative

Ciprofloxacin9, 13, 16, 35, 47, 54, 106, 107 I/III III II/IV II/III/IV IV III -5.41±0.2 -5.21 70±4 15, 16, 20, 37, 54 250 750 35 - Antibacterial

SI4


Drugb WHO

BCS1

BCS

in 2, 3

BCS

in 4

BCS

in 5

BDDCS

in 6

PBC LogPapp

( AB)

LogPapp

(BA)

Fac

%

Fa Ref. Dmin

mg

Dmax

mg

Smina

mg/ml

Smaxa

mg/ml

Therapeutic

category

Cisapride43

II II II II -4.52 -4.57 99±1 20, 21

5 20 0.009 0.186 Gastroprokinetic

Clarithromycin16, 17

III IV -5.46±0.1 -4.73 100 20

250 500 0.082 2 Antibiotic

Clonidine7-10, 15, 16, 24, 27, 46, 59, 84

I/III III I -4.51±0.2 -4.52 97±4 19-21, 25

0.1 0.3 76.9 - Antihypertensive

Clopidogrel bisulfate108

II II IV -6.88 >50 109

- 75 0.051 0.508 Antithrombotic

Clozapine16, 55, 69

II II II -4.51±0.2 -4.74 90±13 19, 37, 110

25 100 0.19 0.2 Antipsychotic

Codeine13, 16

III I/III III I I -4.28±0.4 -4.30 94±1 19,

21

- 30 10 47.62 Analgesic

Colchicine16, 17

III III I III -6.05±0.6 -5.10 55±10 63, 98

- 0.6 43.48 45 Gout medicine

Cortisone11

I I -4.51 - 25 0.216 0.28 Antiinflamatory

Cycloserine59

I/III III III -5.44 72 19, 59

- 250 100 - Antibiotic

CyclosporineA10, 17, 43, 69, 82, 111

III/IV II II II IV -5.80±0.5 -5.43 40±5 63, 83, 112

25 100 0.027 0.04 Immunosuppressant

Cymarin55, 65

III -5.58±0.2 47 19,

21

- 0.3 0.099 - Cardioglycoside

Danazol11, 73, 113

II II II II -4.38±0.4 -5.11 35±17 38, 114, 115

100 200 0.000 0.001 NSAID

Darunavir116

II IV -4.92 -4.36 >80 117, 118

300 600 0.15 - Antiviral

Dasatinib67

II II -4.79 Rapid (d) 20 100 vss 1 Antineoplastic

Desipramine7-10, 12, 13, 15, 24, 27, 46,

69

I I I I -4.53±0.2 -4.61 96±9 19-21, 28,

29, 37, 39

10 200 s 100 Antidepressant

Dexamethasone8-16, 24, 25, 45, 46, 84,

102

I/III I/III I I -4.75±0.5 -5.04 92±8 19-21, 28,

29

0.5 6 0.121 0.261 Antiallergic, hormone

Dextromethorphan119

I I -4.74±0.3 -4.77 Good (d) 30 60 15 - Antitussive

Diazepam8-12, 15, 25, 46, 111

I I/II I I I I -4.24±0.4 -4.75 99±1 19-21, 29, 37

2 10 0.05 0.066 Anticonvulsant

Diclofenac13, 26

II II I II -4.69 -4.67 96±6 19-21, 37, 39,

76, 98, 120

25 50 0.002 9 NSAID

Didanosine32, 33

III III III III III -6.60 46±4 20, 32, 33

100 200 27.3 - Antiviral

Diflunisal26

II II II II -4.74 -4.66 90 19

250 500 0.003 0.006 Antiinflamatory

Digoxin11, 13, 16, 32, 69, 73, 121

I I/III I II III III -5.82±0.5 -4.97 74±20 17, 20, 42,

120

0.12

5

0.25 0.027 0.049 Cardioglycoside

Diltiazem9, 11, 12, 15, 82, 100, 104

I I I I -4.41±0.2 -4.51 92±4 15, 19-21, 28,

29, 37, 39


Diphenhydramine101, 122

I I I I -4.27 95±7 37,

103

(d) 25 50 3.06 1000 Antihistaminic

Dipyridamole16, 17, 113

II IV -4.84±0.4 -4.52 61±4 17, 19, 38, 63

25 75 0.012 29.2 Antithrombotic

Dicloxacillin54

I III III III -6.69 79±25 20, 37, 123

250 500 fs 1000 Antibacterial

Disopyramide102, 124

I I III III -5.37 88±6 19, 20, 125

100 150 6.774 fs Antiarrhythmic

Domperidone16, 17, 113

II IV -5.41±0.2 -4.4 94±1 19, 20

10 20 0.006 0.01 Antidopaminergic

Doxycycline35, 65

I III/IV I III I -4.76 97±4 20, 37, 39

50 100 0.63 1087 Antibiotic

Efavirenz113

II/IV II II/IV II II -4.05 67 126

, (d) - 600 0.005 0.1 Antiviral

Emetine16, 17

III -5.69±0.1 -5.21 - 20 s >100 Antibiotic

Enalapril10, 13, 54, 82

III I/III I I III -6.08±0.8 40 19, 39, 54,

115

2.5 20 25 - Antihypertensive

SI5


Drugb WHO

BCS1

BCS

in 2, 3

BCS

in 4

BCS

in 5

BDDCS

in 6

PBC LogPapp

( AB)

LogPapp

(BA)

Fac

%

Fa Ref. Dmin

mg

Dmax

mg

Smina

mg/ml

Smaxa

mg/ml

Therapeutic

category

Enalaprilat9, 13, 15, 16 III III -6.47±0.7 -6.66 18±10 20, 115 2 8 3.48 - Antihypertensive

Enoxacin54, 69 IV IV -5.31±0.2 -5.28 70 54 200 400 0.6 2.67 Antineoplastic

Entacapone79 II IV -5.6 (FN?) 100 37 - 200 0.017 1.75 Antiparkisonian

Erlotinib67 II II -4.47 25 150 0.4 - Antineoplastic

Erythromycin8-10, 13, 15, 17, 24,

35, 51, 69, 82

IV I III II/III III IV -5.94±0.6 43±11 19, 20, 39, 51 250 500 0.812 2.1 Antibiotic

Exemestane113, 127 II IV -5.26 72 126 - 25 pi 0.08 Antineoplastic

Ephedrine100 I/III I III III -4.99 -5.09 90 15 30 120 5.54 63.62 Antiasthmatic

Estradiol8-10, 46, 82, 84 I/III I I -4.73±0.05 0.5 2 0.009 0.09 Estrogen

Ethinylestradiol35 I/III I I/III I I I -3.42 100 19, 21 0.03 1 0.011 - Estrogen

Ethionamide16 I/III I -4.40 -4.60 90 19 - 250 ss 1 Antituberculosis

Etodolac26 II II -4.64±0.02 -4.60 72±2 19, 103, (d) 400 600 0.04 - NSAID

Etoposide16, 54, 55, 65 II/IV III IV -6.15±0.7 -5.40 52±2 15, 20, 37, 39 50 100 0.115 0.2 Antineoplastic

Etoricoxib128 II II -4.28 -4.29 100 19 30 120 0.15 13.21 Antiinflamatory

Famotidine11, 13, 65 III/IV III III III -5.94±0.03 43±7 19, 21, 37, 39 20 40 1 1.12 Antihistaminic

Felodipine8-10, 15, 16, 43, 84 II II -4.64±0.02 94±6 15,19-21,28, 29 2.5 10 0.001 0.019 Antihypertensive

Fenoprofen26 IV -4.95±0.1 -4.86 85 19 200 600 0.1 - Antiinflamatory

Fenoterol13, 16 III -6.11 -6.13 60 19 2.5 5 s 41.4 Antiasthmatic

Fexofenadine17, 23, 70, 129, 130 I III III III -6.61±0.3 -5.03 58 98 60 180 1.51 - Antihistaminic

Flecainide13 III I -4.42 81 19-21, 37 50 150 48.4 - Antiarrhythmic

Flurbiprofen22, 23, 26 II II II II -4.65±0.2 -4.62 95 19 50 100 0.007 0.011 Antiinflamatory

Fluconazole8, 9, 13, 15, 17, 24, 84,

92

I III III III I -4.59±0.2 -5.17 95±4 15,19-21,28, 29, 37

50 200 8 10 Antifungal

Fluoxetine17, 73, 111 I I I I -4.55±0.7 -4.88 88±11 19, 21, 63, 111,

131

10 20 15.2 50 Antidepressant

Fluparoxan14, 15, 22, 55 I -3.76±1.4 100 14, 15 - 8 s 100 Antidepressant

Flupenthixol51 III -4.88 >90 51 0.25 1 0.352 - Antidepressant

Flutamide132 II II -4.32 90 19 - 125 0.001 - Antiandrogen

Fluvastatin15, 17, 22, 23 I I I -4.77±0.03 -4.14 100 15,19-21,28, 29 40 80 50 80 Anticholesterol

Folic acid51, 133, 134 I/III III II/IV II III -5.77 75 19, 51 1 5 0.662 1.59 Antianaemia

Furazolidone135 IV -4.99 20 100 0.04 0.06 Antibacterial

Furosemide9, 12, 14, 16, 17, 30, 31,

45, 56, 64, 65, 73, 92, 93, 100, 136

II/IV II/IV IV III/IV II/IV IV -5.66±0.7 -5.01 58±7 15, 19-21, 28,

29, 37, 39, 45

20 80 0.073 2.25 Diuretic

Gabapentin9, 11, 13-15, 137, 138 III III III -5.49±0.9 -5.47 56±14 15, 21, 37 600 800 10 100 Anticonvulsant

Ganciclovir8-10, 12, 16, 32, 33, 46,

82, 84, 111

III III III III -6.29±0.4 -5.96 5±3 15, 20, 21, 37 450 500 3.139 6 Antiviral

FN? (False Negative) Results from BBMEC, Caco-2 and MDCKII-MDR1 Cells indicate a BCS class II drug (Int J Pharm. 2010, 402, 27).

SI6


Drugb WHO

BCS1

BCS

in 2, 3

BCS

in 4

BCS

in 5

BDDCS

in 6

PBC LogPapp

( AB)

LogPapp

(BA)

Fac

%

Fa Ref. Dmin

mg

Dmax

mg

Smina

mg/ml

Smaxa

mg/ml

Therapeutic

category

Gefitinib113

II II II -4.48 Varied 42, 113

- 250 0.002 0.01 Antineoplastic

Glipizide55, 139

II/IV II II -4.72 100 19, 20, 51

5 10 0.001 0.027 Antidiabetic

Glutaminic Acid55

III -6.07 49±7 140

, (d) - 550 10.27 10.68 Amino acid

Grepafloxacin107

III -4.89 -4.64 80 141

200 800 s 100 Antibacterial

Griseofulvin8-10, 25, 31, 113

II II/IV II II II II -4.28±0.2 45±20 38, 110, 115, 142,

143, (d)

250 500 0.014 0.02 Antifungal

Guanabenz9, 10, 13-16, 54, 65

I I -4.33±0.4 -4.93 78±3 15, 19, 21, 29


Guanoxan9, 10, 13, 15

III -4.82±0.2 50 19, 21

5 50 ss 10 Antihypertensive

Haloperidol17, 27, 69

III/IV II II/IV II II -4.74±0.04 -4.80 100 19, 20

1 20 0.037 - Antipsychotic

Hydralazine105, 144

III III III I I -4.82 95±5 19, 144

, (d) 10 100 44.2 - Antihypertensive

Hydrochlorothiazide7-9, 12-14, 16,

26, 30, 45, 65, 82, 84, 92

III III/IV III III/

IV

III III -6.07±0.2 -5.72 70±10 15, 19, 26, 29, 37,

39, 45, 51

10 50 0.6 2.501 Diuretic

Hydrocortisone7-14, 47, 65, 69, 138

I I -4.54±0.22 -4.71 90±5 15,

19, 29, 39


Ibuprofen8-13, 24, 26, 27

II II II II II II -4.31±0.4 -4.71 93±7 15, 19-21, 29, 37


Ibuproxam22

II -4.63 - 400 0.17 0.2 Antiinflamatory

Imatinib17, 67

II II IV -4.89 -5.28 99±1 19, 37

400 600 1 - Antineoplastic

Imipramine8, 9, 16, 24, 27, 65, 111, 145

I I I I -4.52±0.3 -4.72 98±2 15, 19, 21, 28, 29,

39

25 50 50 - Antidepressant

Indinavir16, 17

II/IV I IV II II IV -5.68±0.2 -4.66 62.5 63

- 400 0.015 - Antiviral

Indobufen23

II II -4.39 100 19

100 200 0.032 - Antithrombotic

Indomethacin8-10, 12, 26, 27, 35, 73, 86

II II II II -4.45±0.3 -4.58 100 15, 19, 20, 81


Irbesartan38

II II II -3.89 100 19, 37

, (d) 75 300 0.08 0.11 Antihypertensive

Isoxicam55, 69

II -4.61 -4.75 100 19-21

- 200 0.04 - Antiinflamatory

Isradipine13

II II -4.05 91±2 19, 21, 37


Ivermectin17

II/IV II II/IV I IV -6.10 -5.02 57±4 19

, (d) 3 6 0.005 Antifilarial

Ketanserin81

II II -4.44 100 19, 20, 81, 146

- 40 0.05 - Antihypertensive

Ketoconazole11, 16, 55, 69, 73, 113

II II II II -4.62±0.3 -4.96 76 19, 63, 39

, (d) - 200 0.08 - Antifungal

Ketoprofen9, 11, 13, 14, 16, 26, 56, 64,

65, 113

II I II II -4.39±0.3 -4.68 96±4 15, 19-21, 28, 29


Ketorolac26

I I III III -5.37 -4.74 95±5 19-21

- 10 0.11 25 NSAID

Ketotifen129

I III -4.95 90 19

- 1 sps 10 Antihistaminic

Labetalol7-14, 82

I I I -4.65±0.3 -4.38 94±3 15, 19-21, 28, 29

100 300 16 20 Antihypertensive

Lamivudine147

I III I/III III III -5.42±0.05 -5.01 93±7 19, 20, 37

150 300 149.6 - Antiviral

Lamotrigine14-16

II II II -4.32±1 -4.80 91±14 15, 19-21, 28, 29

25 200 0.17 - Anticonvulsant

Lansoprazole13, 69

II II II II -4.43±0.2 -4.51 92±8 15, 19-21

15 30 0.001 0.137 Antiulcerative

Levodopa11, 15, 22, 51

I III I I I III -5.82±0.5 90±10 15, 51, 63, 83

100 250 1.65 3.8 Antiparkisonian

Levothyroxine51

III I II III -5.52 80 51

0.025 0.3 0.093 0.15 Thyroid hormone

SI7


Drugb WHO

BCS1

BCS

in 2, 3

BCS

in 4

BCS

in 5

BDDCS

in 6

PBC LogPapp

( AB)

LogPapp

(BA)

Fac

%

Fa Ref. Dmin

mg

Dmax

mg

Smina

mg/ml

Smaxa

mg/ml

Therapeutic

category

Lidocaine9, 10, 73, 82, 92

I I I I -4.39±0.3 -4.88 98 19, 37

20 40 3.984 - Anesthetic

Lincomycin13

III III -7.09 28 19

100 500 50 - Antibiotic

Lisinopril9, 14, 16, 92

III III III III -6.50±0.6 27±2 15, 20

,(d) 2.5 40 97 - Antihypertensive

Lisuride102

I -4.21 100 148

0.2 0.5 s 100 Antiparkisonian

Lomefloxacin69

I/III I III III -4.80 -5.19 95 19

, (d) - 400 1.64 27.23 Antibiotic

Loperamide16, 17, 69, 149

III III -4.97±0.4 -4.85 40 63

,** - 2 1.4 - Antidiarrheal

Lopinavir150

II/IV II II II -4.39 - 200 pi - Antiviral

Loracarbef14

III III -6.62 100 15, 28, 29

200 400 41 - Antibiotic

Lobucavir32, 33

IV -6.06 39±15 32, 42

200 400 0.8 - Antiviral

Lorazepam111

I I I -4.54 98±3 19-21

0.5 2 0.054 0.08 Anticonvulsant

Losartan53

I II IV -6.09 80 19, 20

25 100 0.048 - Antihypertensive

Lovastatin43

II II II IV -4.84 -4.94 30 19, 20

,(d) 10 40 0.002 - Antihyperlipidaemic

Loxoprofen23

I I -4.35 - 60 vs 1000 Antiinflamatory

Mebendazole69

II/IV II II/IV II/IV II II -4.51 -4.64 100 19, 20

100 500 0.035 0.071 Antibiotic

Mefenamic acid26

II II -4.75 -4.65 90 19


Meloxicam7-9, 26, 151

II/IV II II -4.66±0.2 -4.82 90 19-21, 37

7.5 15 0.001 0.005 Antiinflamatory

Metaproterenol13, 65

III -6.17±0.4 43 19, 21

10 20 9.7 100 Antiasthmatic

Metformin16, 32, 33, 65

III III III III III III -5.11 -5.12 54 19, 37

500 1000 vs 1000 Antidiabetic

Methadone43

I I -4.66 -4.58 91±10 19-21, 37

5 10 120 - Opioid

Methotrexate9-13, 16, 24, 32, 34,

54, 69, 81

III III III III/IV III III -6.40±0.6 -6.40 61±28 15, 20, 32, 37, 39, 63

2.5 15 0.45 2.6 Antirheumatic

Methyldopa11, 22, 23, 152

III III III III III -6.62 41 20, 39,

83


Methylprednisolone14, 16, 17,

54, 153

I III -5.02±0.4 -4.85 82 15, 19-21, 28, 29


Methylscopolamine7-11

III -6.01 -5.69 Poor (d) - 5 fs 1000 Anticonvulsant

Metoclopramide111

I/III I/III III I -4.65 96±7 19, 20, 37, 51

5 10 0.2 0.38 Antiemetic

Metolazone9, 32, 33, 47

III -5.21±0.2 -4.89 64 15, 19-21

2.5 10 0.062 0.1 Diuretic

Metoprolol8-10, 16, 26, 31, 32, 46-

48, 56, 64, 70, 72, 75, 84, 92, 154

I I I I I -4.69±0.4 -4.66 97±2 15, 18-21, 29, 37, 39


Midazolam45, 111

I I I I -4.40±0.3 -4.49 100 19, 20, 37

- 15 0.054 10.3 Anticonvulsant

Minoxidil13

I III -4.99 97±1 19, 21

2.5 10 2.2 - Antihypertensive

Morphine11, 27

I/III I/III I/III I III -5.20 95±5 19, 37

15 30 57.14 - Opioid

Nadolol8-11, 13, 14, 32, 45, 54

III III III III -5.93±0.5 -5.99 37±10 15, 18-21, 39, 81


Naproxen17

II II II II -4.37±0.3 -4.55 99 15, 19, 20, 29, 37, 39

250 500 0.115 300 Antiinflamatory

Nelfinavir14

I/II IV II II IV -6.15 -5.77 250 625 ss 4.5 Antiviral

Netivudine14

III -5.17 28 15, 19, 37

- 200 5.92* - Antiviral

*Solubility calculated by method of Meylan et al.155

(Also used in Ref.6); **Compound of borderline class,63 and presents varied Papp (4-22×10

-6 cm/s)

SI8


Drugb WHO

BCS1

BCS

in 2, 3

BCS

in 4

BCS

in 5

BDDCS

in 6

PBC LogPapp

( AB)

LogPapp

(BA)

Fac

%

Fa Ref. Dmin

mg

Dmax

mg

Smina

mg/ml

Smaxa

mg/ml

Therapeutic

category

Nevirapine7, 9, 10, 12, 82, 156

II II II II II -4.37±0.7 100 19

- 200 0.1 0.171 Antiviral

Nicardipine102, 111

I I I -4.74±0.1 -4.92 97±3 19, 20,

17, 157


Nicotine7-11, 84

I I -4.39±0.3 100 19-21

- 4 vs 1000 Opioid

Nifedipine16, 43, 69, 111

II II II I II II -4.38±0.2 -4.46 94±6 19, 20, 76


Nisoldipine43

II -4.70 91±3 19-21, 76, 123


Nitrendipine9, 10, 92, 113

II II -4.35±0.5 89±8 19, 21, 37, 39, 76, 123


Nitrofurantoin17

II IV II IV IV -6.09 -4.73 95 17, 19, 50 100 0.14 0.272 Antibiotic

Nordazepam9, 47

I II -3.70±0.4 99 19-21

7.5 15 0.057 - Anticonvulsant

Norfloxacin13, 16, 54, 69, 70, 93, 105

IV IV -5.67±0.2 -5.24 50±15 17, 21, 29, 98, 158-161

- 400 1 1.2 Antibiotic

Ofloxacin13, 69

I IV II III I -4.79 100 19, 20

, (d) 200 400 3.54 60 Antibiotic

Olopatadine23

I/III III III -5.01 Oral* - 5 2 10 Antihistaminic

Olsalazine8-10, 17, 32

IV -6.59±0.5 3 29, 32, 72, 83

, (d) 250 500 0.082 - Antiinflamatory

Omeprazole13, 16, 69

I I -4.26±0.08 -4.49 90±10 19-21, 37, 76


Ondansetron14

I/III I I -3.96 100 15, 19-21, 28, 29


Orphenadrine135

I I -4.24 97±4 19, 135

- 100 10 - Anticholinergic

Ouabain11

III -6.96 1.4 21, 83, 162

2 8 13 - Cardioglycoside

Oxazepam9, 12, 13, 16, 47

II II -3.91±0.4 -4.86 95±4 15, 19-21, 37

10 30 0.05 0.179 Antipsychotic

Oxprenolol8-10, 13, 14, 48, 72, 81

I I -4.02±0.3 93±3 15, 19, 21, 28, 29, 39


Oxaprozin26

II II II II -4.48 -4.40 98 19

- 600 0.004 1.7 Antiinflamatory

Papaverine163

II -4.45 -4.29 90 19, 20


Paracetamol13-15, 45, 54, 55

I IV III I I -4.41±0.7 -5.04 89±9 15, 19-21, 28, 29, 164

500 1000 20 122.8 Antiinflamatory

Penicillin V14, 165

I/III IV IV -6.85±0.04 45 14, 28, 29, 110

250 500 0.25 - Antibiotic

Pentoxifylline101

I I -4.18 95 19

- 400 77 191 Antiinflamatory

Pefloxacin139

I I -4.60 95 19, 20

- 400 11.39# - Antibiotic

Phenazopyridine35

II II IV II -3.55 90 19

100 200 0.388 1 Analgesic

Phenobarbital135, 166

I I/III I I I I -4.63 100 19, 20, 37


Phenylalanine9, 15, 64, 71, 73, 138

III I I -4.76±0.2 100 167, 168

- 500 30 - Amino acid

Phenytoin7-12, 14, 16, 53, 54, 82, 84,

92, 105, 138, 169

II II II II II II -4.31±0.2 -4.34 96±5 15, 19-21, 28, 29, 37,

39


Pimozide8, 9, 55, 84, 92, 170

I IV -6.18 70 19

, (d) 1 2 0.003 0.008 Antipsychotic

Pindolol7-10, 12-14, 16, 32, 46, 47, 82,

84, 92

III I -4.42±0.3 93±5 15, 19-21, 28, 29, 37,

39, 81


Pirenzepine7-10, 111

III III -6.33±0.3 -5.72 25±5 37, 162

25 50 50 - Antiulcerative

Piroxicam8-10, 12, 13, 25, 26, 64, 136

II II II II -4.38±0.2 -4.59 100 19, 21


Pivampicillin60

II -4.49 ** 350 700 pi 0.035 Antibiotic # solubility calculated by method of Meylan et al.

155 (Also used in Ref.

6); *Administration by the nasal, oral (few), intravenous (few), and topical ocular routes (Falcon

Pharmaceuticals, Ltd.); **High bioavailability 87-94% (J. Pharmacokinet. Biopharm. 1979, 7, 429–451; J. Pharm. Sci. 1973, 62, 69–76)

SI9


Drugb WHO

BCS1

BCS

in 2, 3

BCS

in 4

BCS

in 5

BDDCS

in 6

PBC LogPapp

( AB)

LogPapp

(BA)

Fac

%

Fa Ref. Dmin

mg

Dmax

mg

Smina

mg/ml

Smaxa

mg/ml

Therapeutic

category

Pranlukast38

II II -4.60 - 225 0.001 0.088 Antiasthmatic

Practolol8-10, 13, 14, 47, 48, 72, 82, 84, 92

III -5.62±0.3 95±5 15, 19-21, 28, 29

200 400 4.47 - Antiarrhythmic

Pravastatin9, 16, 33, 92

I/III III III III -6.91±0.7 -5.98 34 15, 19, 20, 37

10 80 300 - Antihyperlipidaemic

Prazosin8-10, 13, 16, 17, 24, 55, 69, 73

I III -4.89±0.4 -4.62 86 20, 21, 28, 29, 37


Pranoprofen61

II -4.39 - 75 pi Antiinflamatory

Prednisolone69, 153

I I I I I III -5.37±0.09 -4.92 98±2 15, 19-21, 29, 39

2.5 25 0.169 0.352 Antiinflamatory

Primaquine35

I I/III I I I I -3.75 R&C.* - 15 718.4 - Antimalarial

Progesterone7-10, 13, 25, 69, 73, 82, 84, 92,

171

II II -4.28±0.3 -4.54 96±6 15, 21, 28, 29, 39

50 200 0.013 0.015 Hormone

Promazine7-10, 12, 53, 69, 111

I I I I -4.38 -4.59 100 123

, (d) 50 100 333.3 - Antipsychotic

Promethazine35

I I III I I -3.78 97±3 19,

123

, (d) 25 50 300 - Antihistamine

Propranolol7-10, 12-14, 16, 24, 26, 40, 46,

56, 71, 73, 74, 86, 91, 93, 100, 105, 111, 172-177

I I I I I I -4.44±0.2 -4.58 95±5 15, 19-21, 28,

29, 37, 39


Propylthiouracil13, 14, 16

I III III I I I -4.17±0.3 -4.65 90** 20

, (d) - 50 1.2 1.204 Antihyperthyroid

Pyridoxine178

I III I I -4.52 95±5 98

25 100 222 282 Vitamin

Pyrimethamine101

III/IV II/IV III I -4.23 -4.00 100 179

, (d) - 25 0.194 0.826 Antimalarial

Quinidine Sulfate8-10, 12, 13, 16, 24, 27,

43, 54, 69

I/III I I I I -4.68±0.3 -4.52 95±5 20, 37, 39, 180,

181, (d)

200 300 11.1 - Antimalarial

Raffinose9, 32, 33, 47, 89

III -7.31±0.2 0.3 15, 19, 21, 39

100 750 213.2 229.8 Cardiac function

Raloxifene182

II II II IV -5.80±0.4 60 (d) - 60 0.013 0.3 Antiosteoporotic

Ranitidine7-13, 16, 26, 27, 30, 31, 54, 56, 69,

176

III III III III III -5.95±0.4 -5.44 60±7 12, 15, 20, 21,

28, 29, 37, 39, 81

150 300 550 660 Antiulcerative

Rapamycin; Sirolimus 183

II IV -5.00 Rapid. (d) 1 2 0.003 - Immunosuppressant

Rebamipide184

II IV -6.94 Poorly (d) - 100 pi - Antiulcerative

Remikiren9, 10, 82, 92

III -6.13 Poorly (d) - 600 200 - Antihypertensive

Repaglinide43

II I -4.62 -4.84 100 19, 20, 37

0.5 2 0.09 - Antidiabetic

Reserpine16, 17, 101

I III I III -5.37±0.1 -5.65 50 63

0.1 0.25 0.073 - Antihypertensive

Riboflavin178

I III I IV I -4.66±0.2 -4.71 80 20, 185

, (d) 50 100 100 - Vitamin

Rifabutin43

II IV -5.02 -4.50 53 20, 186

- 150 0.19 - Antiviral

Rifampicin; Rifampin59, 121

II II II IV -5.40±0.3 -5.08 Dose# (d) 120 300 1 107 Antileprosy

Rifapentine59, 187

IV -4.93 High (d) - 150 pi 0.021 Antiviral

Risperidone27, 188

II I I -4.79±0.16 98±2 19, 20, 37

0.25 4 0.25 - Antipsychotic

Ritonavir16, 17, 53

II/IV II IV II II IV -5.51±0.1 -4.49 68±2 17, 20, 63

50 100 pi Antiviral

Rofecoxib26

II II II -4.62±0.08 -4.69 (d) 12.5 50 0.001 0.011 Antiinflamatory

Rosuvastatin17

IV III -6.30 -5.12 50 20, 120

sps - Anticholesterol

Roxithromycin55

IV -5.27 -5.01 84.5 189

, (d) 0.1 Antibiotic

*Readily and completely absorbed (absolute bioavailability 96±8% 190, 191

); **Fa = 100% (J. Pharmacol. Exp. Ther. 1972, 183, 440-448); #Dose-dependent absorption.

SI10


Drugb WHO

BCS1

BCS

in 2, 3

BCS

in 4

BCS

in 5

BDDCS

in 6

PBC LogPapp

( AB)

LogPapp

(BA)

Fac

%

Fa Ref. Dmin

mg

Dmax

mg

Smina

mg/ml

Smaxa

mg/ml

Therapeutic category

Salbutamol192

I III I III III -6.52 -6.25 100 20

, (d) 2 4 17.71 17.95 Antihistamic

Saquinavir9, 10, 12, 92, 121

II/IV I IV II II IV -6.28±0.3 -4.92 16±11 16, 19, 24, 112, 124

,

(d)

- 500 0.036 0.055 Antiviral

Scopolamine7-10, 12, 13, 46,

82, 84, 92

I I -4.52±0.3 -4.77 93±4 15, 19-21, 28, 29, 37

0.4 10 666.7 - Anticholinergic

Scutellarin193

III -5.60±0.1 -5.89 - 80 23.65 - Antihypertrophic

Sildenafil9, 43, 47, 111

I I I -4.26±0.3 -4.34 92 20, 47

, (d) 50 100 3.5 - Anti-erectile dysfunction

Simvastatin43

II II IV -5.17 -5.32 14 112

, (d) 20 80 0.03 0.1 Antihyperlipidemic

Sorivudine194

III -5.39 82 83

- 50 fs 100 Antiviral

Sotalol14, 15, 22, 55

III III -5.38 95 15, 19-21, 28, 29

80 240 137 - Antiarrhythmic

Sparfloxacin107

I I -4.73 -4.62 95±5 19, 20

- 200 1.1 Antibiotic

Spironolactone113

III/IV II II/IV II II II -4.31 100 83, 126, 195, 196

(d) 25 100 0.028 - Antiandrogen

Stavudine (d4T)174

I III I III III -5.35 100 83

, (d) - 40 104.7 - Antiviral

Sulfadiazine16

III/IV IV II/IV IV IV -5.13 -5.24 75±12 16, 19, 20, 185

,(d) - 500 0.12 0.18 Antibacterial

Sulfamethizole54

IV IV -5.84±0.2 85 19, 54, 123, 185

250 500 0.884 1.05 Antifungal

Sulfamethoxazole55

II IV II II II -4.59±0.2 100 19, 20, 37

400 800 0.463 1.4 Antibacterial

Sulfapyridine197

II -4.67 -4.71 - 500 0.45 1.528 Antibiotic

Sulfasalazine81, 197

IV II II/IV II IV -6.51 13±1 17, 32, 47, 54, 83,

115, 144, 185, 198-

201, (d)


Sulfinpyrazone17, 101

II IV -5.92±0.08 -5.08 92±8 17, 19, 20,

100 200 0.031 Antiplatelet

Sulfisoxazole55

IV II -4.77±0.2 100 144

- 800 0.292 0.33 Antibiotic

Sulindac13, 16, 17, 26, 105

II IV -5.27±0.1 -4.91 90 19, 21, 51


Sulpiride10, 13, 33, 47, 54, 82,

92, 105

III III -6.30±0.2 38±6 15, 19-21, 37, 39

- 200 2.28 - Antipsychotic

Sumatriptan8, 9, 11, 13, 16,

17, 84, 92, 100

III I III -5.65±0.3 -5.63 67±11 15, 19-21, 28, 29, 37

25 100 21.4 - Antimigraine

Tacrolimus17, 43

II II II IV -5.15±0.8 -4.81 15 20

0.5 5 0.001 0.008 Immunosuppressant

Talinolol73, 121

II II III III -5.12±1.2 -4.97 65 20

50 100 1.23 4.5 Antiarrhythmic

Tamoxifen53, 69

I II II I I -4.62±1.3 -6.52 100 19

10 20 0.5 Antineoplastic

Telithromycin189

II IV -5.74±0.6 -5.15 77 189

, (d) 300 400 0.8 Antibiotic

Telmisartan7-9, 12, 13, 84, 92

II II II -4.75±0.9 -4.41 90 19-21


Tenidap8, 9, 16, 24, 84, 92

II -4.33±0.07 -4.81 90 15, 19, 21, 28, 29

- 120 0.014 - Antiinflamatory

Tenoxicam13, 69

I II -4.75±0.3 -4.56 100 19-21, 37


Terazosin13

I/III I III -5.09 90±2 15, 19-21, 28, 29, 37

,

(d)


Terbinafine16

I II IV -5.74 -5.44 80 19

- 250 0.005 - Antibacterial

SI11


Drugb WHO

BCS1

BCS

in 2, 3

BCS

in 4

BCS

in 5

BDDCS

in 6

PBC LogPapp

( AB)

LogPapp

(BA)

Fac

%

Fa Ref. Dmin

mg

Dmax

mg

Smina

mg/ml

Smaxa

mg/ml

Therapeutic

category

Terbutaline8, 10, 12, 13, 16, 32,

45, 54, 64

III III -6.23±0.5 50±19 15, 16, 19-21, 32, 37, 39,

44, 45, 115, 144, 199,

(d)

2.5 5 213 - Prevent premature

Terfenadine16

II II II IV -5.26 -5.82 70 63

, (d) - 60 0.0001 0.006 Antihistamic

Testosterone7-12, 54, 69, 100

II II -4.32±0.4 -4.44 99±0.7 15, 19, 28, 29

30 40 0.056 - Hormone

Tetracycline54, 65, 93

III III III III -4.89±0.6 74±8 37, 65, 123

, (d) 50 500 27.7 35 Antibiotic

Thalidomide202

II II -4.70 High** 50 200 0.545 - Antiinflamatory

Theophylline9, 10, 13, 31, 35,

45, 53, 54, 56, 70, 73, 82, 92, 93, 111

IV I I I I -4.42±0.2 -4.53 98±2 15, 20, 37, 45, 76, 81, 102,

124, 199, 203(d)

100 600 10 - Bronchodilator

Tiacrilast9, 10, 82, 92

III -4.90 99 15

150 750 3.078# - Antihistamic

Tiaprofenic Acid27

II II -4.41 Compl.* 204

100 300 0.2# - Antirheumatic

Timolol7-11, 13, 16, 84, 86, 92

I/III I I -4.58±0.2 -4.81 95±5 15, 18-21, 37, 39, 51

5 20 2.74 - Antiarrhythmic

Tinidazole51

I I -4.52 100 19, 20, 51, 103

- 500 19.9# - Antibacterial

Tolbutamide55, 205

II II -4.28 87±2 19-21, 37

200 500 0.14 0.819 Antihyperglycemic

Tolcapone79

II II -4.20 100 200 0.05 0.115 Antiparkisonian

Tolmetin26

II IV -5.09±0.03 -5.04 95±6 18, 19, 185


Topiramate136

III III I -4.55 86 19, 21, 206

25 200 9.705 9.8 Antidepressant

Topotecan17, 121

III III -6.07±0.1 -4.95 30 17

0.25 1 1 - Antineoplastic

Tramadol207

I I I -4.41±0.1 -4.30 95±5 19-21, 37

- 50 30 100 Analgesic

Tranexamic acid11

III -6.04 55 15, 19

500 650 167 - Antihiperfibrinolisis

Trazodone43, 101

II II -4.41±0.2 -4.66 100 15, 19, 37

50 300 0.2 0.276 Antidepressant

Triazolam43

I I -4.55 -4.77 85 19, 20

, (d) 0.125 0.5 0.03 - Antidepressant

Trifluoperazine16

I III -6.30 -6.00 100 19, 103

1 10 50 - Antipsychotic

Trimethoprim13, 14, 16, 69

II IV II III III II -4.43±0.3 -4.76 98±1 15, 19-21, 28, 29,

83, 110,

203, (d)

100 200 0.787 1.37 Antibiotic

Trovafloxacin8, 9, 84, 100

II -4.52 88 15, 19, 28, 29

, (d) 100 200 0.02 - Antibiotic

Valacyclovir32, 208

III I III -5.72±0.1 68 209

, (d) 500 1000 174 - Antiviral

Valproic acid8-10, 12, 100

I III II I I I -4.32 100 15, 20, 21, 29, 37

125 500 2 - Anticonvulsant

Valsartan16, 17

II III IV IV -6.25±0.2 -5.80 55 19-21


Verapamil9, 11-13, 16, 26, 27,

35, 43, 56, 65, 69, 70, 86, 121, 210

II I I/II I I I -4.23±0.5 -4.58 98±2 15, 17, 20, 21, 39, 81, 120,

199, 203, (d)


Viloxazine16

I -4.39 -4.72 98±2 19, 83, 209

50 200 1.3 - Antidepressant

Warfarin8-10, 12, 13, 16, 35, 45,

53, 82, 86, 93

I I I/II II II II -4.44±0.2 -4.63 95±3 15, 20, 21, 28, 29, 37

1 10 0.017 0.04 Anticoagulant

Xamoterol13

III -6.72 8.6±4.7 211

, (d) 50 200 16.96 - Antiinflamatory

*Completed absorption; # alculated solubility by method of Meylan et al.

155 (Also used in Ref.

6) ; **dose-dependent, no food-effect but slow absorption.

212

SI12


Drugb WHO

BCS1

BCS

in 2, 3

BCS

in 4

BCS

in 5

BDDCS

in 6

PBC LogPapp

( AB)

LogPapp

(BA)

Fac

%

Fa Ref. Dmin

mg

Dmax

mg

Smina

mg/ml

Smaxa

mg/ml

Therapeutic

category

Yohimbine213

III -4.81 -4.70 2 5 0.277 10 Antidepressant

Zaltoprofen22, 23

II -4.40 80 160 pi - Antiinflamatory

Zidovudine8-10, 12, 14,

25, 35, 65, 82, 84, 92, 147

I III I I I I -4.39±0.03 -4.23 100 15, 28, 29, 37

, (d) - 300 20.1 30.1 Antiviral

Ziprasidone8, 9, 24, 84, 92

II IV -4.91 60 15, 19, 29,

83

, (d) 20 80 0.3 - Antipsychotic

Zolmitriptan154, 214

III I III -6.00 92 20,

63

2.5 5 12.6 20 Antidepressant

Zolpidem43

I I I -4.49 -4.45 98±2 19, 21, 37

5 10 23 - Antidot

Zomepirac55

I -4.61 100 19, 215

- 100 ss 10 Antipyretic

aThe minimum and maximum aqueous solubility (mg/ml) values between pH ranges 1.2-6.8 at 37°C (in cases that specified temperature is not available, range of 25-

37°C has been conservatively used) were mainly taken from references,6, 216-218

PhysProp database (available at http://www.srcinc.com/what-we-

do/databaseforms.aspx?id=386), ChemIDplus database (available at http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp), and Therapeutic System Research

Laboratories website (http://www.tsrlinc.com/services/bcs/search.cfm). Where solubility data were not available or undefined, guidelines were taken from Kasim et al.2

bReferences where the apparent permeability across Caco-2 monolayer

and some additional information (%Fa, BA, transport mechanism) were revised.

cFraction absorbed values were taken from different references. For drugs that are cited in original published papers, the original data were revised and taken. When the

original data were not available or accessible, the recollected data were used and cited. The average value was calculated as [Average ± SD]. When Fa is given as a range

(e.g. 80-100%), the middle value (e.g. 90%) was used.

(d) Absorption information was obtained from pharmaceutical product: Ambroxol 52

(http://www.dotpharma.in/solvent.html) , Artesunate

(http://apps.who.int/prequal/whopar/whoparproducts/MA044part4v2.pdf), Baclofen (Bioavailability 70-80%, Lioresal® - Novartis Pharmaceuticals Australia Pty

Limited, updated 13 September 2010), PK/DB database (available at http://www.pkdb.ifsc.usp.br); Ceftibuten (rapidly absorbed (75-90%), Indian Pediatrics 1999, 36,

901-904); Dasatinib (http://www.ema.europa.eu/ema/pages/includes/document/opendocument.jsp?webContentId=WC500056995); Dextromethorphan (Flucold® -

Cosmos Limited); Efavirenz: the oral absorption of efavirenz in the fasted state is considered to reach a ceiling at high doses (1200 mg) because the relative

bioavailability (fasted/fed, estimated) was 100% at 100 mg but 67% at high dose (1200 mg) (Sustivai® - NDA no. 020972, 1998, DuPont Pharmaceuticals Company,

Wilmington, DE, USA);113

Etodolac high bioavailability was found (>80%);26

Glutaminic Acid (http://bionumbers.hms.harvard.edu/bionumber.aspx?s=y&id=102144&

ver=3); Griseofulvin: slowly, erratically and incompletely absorbed from the gastrointestinal tract in humans;219

Hydralazine: rapidly absorbed after oral administration,

and peak plasma levels are reached at 1 to 2 hours, extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine (hydrALAzine

hydrochloride, USP, - NDC 50111-398, PLIVA®, INC. East Hanover, NJ 07936); Irbesartan: varied absorption profile (Fasted and Fed,42

however it appears as rapidly

and completely absorbed drug (http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=6f08623c-dc4c-4661-9e69-2033d9dce34e); Ivermectin: varied absorption

profile (Fasted and Fed,42

and dose dependent, Stromectol® - Merck & Co., Inc.); Ketoconazole (?): intestinal absorption 6%, Fasted;38, 42

Lisinopril: large intersubject

variable absorption (Lisinopril – NDC 0093-1111-01, TEVA Pharmaceuticals USA); Lomefloxacin: absorbed 95-98% (Maxaquin®- Buffalo Grove, IL: Unimed

Pharmaceuticals, 1999); Lovastatin (Lovastatin, NDC 68084-131-01- Actavis Elizabeth LLC USA); Methylscopolamine: total absorption of 10-25% (DB00462,

DrugBank); Nifedipine: there are some reports of low absorption values (45%,63

64%,37

or 74%;112

however it is well known as a completely absorbed drug, e.g.

bioavailability 84-89%, Nifediac CC® - NDC 0093-1022-93, TEVA Pharmaceuticals USA); Ofloxacin: bioavailability ~98% (Ofloxacin tablet, film coated – NDC

0093-7180-01, TEVA Pharmaceuticals USA); Olsalazine: varied absorption (other works report Fa values of 17%,160

24%,21

or 20%;20

however from Dipentum®

capsules 250mg or tablets 500mg - UCB Pharma Limited profile, 22-33% of an oral dose appears in the urine almost all as metabolite Ac-5-ASA, indicating a very low

uptake of unchanged olsalazine); Pimozide: dose absorption ≥50% (ORAP® - NDC 57844-187-01, TEVA Pharmaceuticals USA); Promazine: a lower absorption was

published (40%);63

Promethazine: a lower absorption was published (25%),63

however this drug is well absorbed (http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?set

http://www.srcinc.com/what-we-do/databaseforms.aspx?id=386

http://www.srcinc.com/what-we-do/databaseforms.aspx?id=386

http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp

http://www.tsrlinc.com/services/bcs/search.cfm

http://www.dotpharma.in/solvent.html

http://apps.who.int/prequal/whopar/whoparproducts/MA044part4v2.pdf

http://www.pkdb.ifsc.usp.br/

http://www.ema.europa.eu/ema/pages/includes/document/opendocument.jsp?webContentId=WC500056995

http://bionumbers.hms.harvard.edu/bionumber.aspx?s=y&id=102144&%20ver=3

http://bionumbers.hms.harvard.edu/bionumber.aspx?s=y&id=102144&%20ver=3

http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=6f08623c-dc4c-4661-9e69-2033d9dce34e

http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?set%20id=a32255f0-0077-489e-bdc6-869aca8cd434

SI13

id=a32255f0-0077-489e-bdc6-869aca8cd434); Propylthiouracil: a Fa value of 75 or76% is commonly reported,14, 19, 28, 29, 83, 159

however its bioavailability is about 85% 167

and it is a readily absorbed and is extensively metabolized drug (Propylthiouracil tablet- NDC 67253-651-10, DAVA International Inc.); Pyrimethamine (Daraprim®

- NDC 0173-0201-55, GlaxoSmithKline); Quinidine: lower Fa values were reported (80-81%),19, 21

its bioavailability varies widely (45 to 100%) between patients

(Quinidine Sulfate tablet – NDC 0185-1047-01/10, Sandoz Inc.); Raloxifene (PK/DB database, available at http://www.pkdb.ifsc.usp.br & Evista® - NDC 0002-4165,

Eli Lilly and Company USA); Rapamycin (Sirolimus): low bioavailability 10% (rat),220

and 14% (Rapamune® tablet – NDC 0008-1031-05/10, Wyeth Pharmaceuticals

Inc.); Rebamipide: BCS class IV drug (J. Control. Release 2006, 111, 27-34); Remikiren (Ro 42-5892): bioavailability <2% (Page 398, Ref221

and Ref222

); Riboflavin is

reported as well absorbed drug with estimated Fa value (USP DI, Thomson MICROMEDEX database 2000, www.thomsonhc.com/); Rifampicin (Rifampin): a greater

dose (600mg) was reported, monograph showed that this is a BCS class II antibiotic 223

(while Papp measurements are 2 or 5.79×10-6

cm/s,59, 121

significantly lower than

current in vitro-in vivo correlation application); Rifapentine appeared with 100% of bioavailability (possible BCS class II),59

or 70% (priftin® - NDC 0088-2100-03,

sanofi-aventis U.S. LLC); Rofecoxib bioavailability of 93% (reported in 26

); Roxithromycin estimated absorption 78-91%, bioavailability 20%

(http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1ff30eb1-95a6-437e-a618-297891c0c03d); Salbutamol: low absorption, bioavailability varies widely (10-

50%);224-227

Saquinavir: estimated Fa is 80%,20

very low absolute bioavailability (4%, Invirase® - NDC 0004-0245-15, Hoffmann-La Roche Inc.); Sildenafil: a lower

absorption was estimated (57%);37

Simvastatin: BCS class II in Ref 228

, bioavailability <5%;229, 230

Spironolactone: lower Fa values were found (58%, Fatsed, dose

200 mg in Ref38

, and 73% in Ref21

); Stavudine: BCS class I in Ref231

; Sulfadiazine: PK/DB database (available at http://www.pkdb.ifsc.usp.br), (?) bioavailability

100%,97, 232

and is readily absorbed from the GI tract (SulfADIAZine tablet - NDC 0185-0757-01, Sandoz Inc. Princeton, NJ 08540); Sulfasalazine: higher Fa values

were found (58-59% in Ref20, 63

, or 62-65% in Ref14, 19, 29

) however, its intestinal absorption extent is reported to be lower than 20% in Ref,39

widely varied (7-17%),73

and even lower than 15% in Sulfasalazine Tablet, USP (0603-5801-04/21/28/32, Qualitest Pharmaceuticals, Huntsville, AL 35811); Telithromycin: a higher Fa value

was reported (90%) in Ref19

, however this drug is well known as a widely varied absorption drug (56-91%);189

Terazosin: lower Fa was found (60% in Ref14

);

Terbutaline: there are varied Fa values, ranging from 25-80%,233

but mostly used are 73% and 60-63%. Only 30%-50% of the dose was recovered from urine and the

remainder from the feces, which may indicate poor absorption (Terbutaline Sulfate Tablets USP - NDC 42291-801-18, AvKARE, Inc.); Terfenadine: very high Fa

values were reported (>95% in Ref 51

or 100% in Ref 19

), and lower intestinal absorption was published as 40% in Ref. It is also known that this compound has relatively

low bioavailability due to its limited solubility in water,234

and the oral absorption of terfenadine was at least 70%.235

Seldane (terfenadine) and Seldane-D (terfenadine

plus pseudoephedrine) were withdrawn from the U.S market in 1997, then from the Canadian market in 1999 and no longer used for prescription in the UK;

Tetracycline: higher Fa values were found in Ref 51

(>80%) and in an estimation in Ref 20

(90%); Theophylline: a lower, widely varied Fa (84±16%) was published;98

Triazolam: higher Fa value was estimated in Ref 37 (100%) and lower Fa value was found in Ref

112 (75%); Trimethoprim: a lower Fa value was estimated in Ref

37

(65%), however oral bioavailability is high (98% 167

or >92% 83

); Trovafloxacin: original data recollected by Wessel et al.29

, a higher value was estimated in Ref 20

and

bioavailability data are varied (65-122%, taking the middle value as 88% in Ref97

); Valacyclovir: a lower Fa value (36%) was reported in Ref 32

, however bioavailability

data was reported as 80-100% in Ref 167

. In pharmacokinetic data of product, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly

completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. The absolute bioavailability of acyclovir after administration of

valacyclovir is 54.5 ± 9.1% as determined following a 1 gram oral dose of valacyclovir and a 350 mg intravenous acyclovir dose to 12 healthy volunteers

(http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=56bf715d-8280-4557-9f98-9693932199e5); Valsartan: lower Fa values were found (24-25%) in Ref,17, 37

mean

absolute bioavailability is 23% (UKPAR valsartan Tablets, PL 24668/0061, Caduceus Pharma Ltd. London, W1U 3RF). In literature, for human, the amount of drug

cleared through bile follows two parts: 75% go to the gallbladder where it was stored during fasted state and the remaining 25% continuously recirculated to the

duodenum, where it was available for reabsorption.236

Verapamil: lower Fa value (28%) was found in Ref 63

however oral bioavailability is 84±4%.98, 167

Xamoterol:

absorbed by the paracellular route with 9% of absorption extent (? Fa) in Ref,237

a higher Fa value (19%) was reported in Ref,209

and a lower Fa value was estimated in

Ref.20

Zidovudine: lower Fa values were reported (90% in Ref17, 238

or 98% in Ref 110

); Ziprasidone: very high Fa values were reported (100% in Ref 37

and 90% in Ref 20

).

http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?set%20id=a32255f0-0077-489e-bdc6-869aca8cd434


http://www.thomsonhc.com/

http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1ff30eb1-95a6-437e-a618-297891c0c03d


SI14

Table SI2. Common in silico parameters for classifying permeability and solubility

Drug Ionica cLogPb cPSAc

(Å2)

ALogPSd ACD/Labse Volsurff Drug Ionic cLogP cPSA

(Å2)

ALogPS ACD/Labs Volsurf

LogS ( mg/ml ) LogS ( mg/ml )

Acebutolol B 1.59 87.7 -0.77 -1.01 0.64 Brompheniramine B 3.26 16.1 -1.90 -0.22 0.18

Aceclofenac A 3.61 75.6 -2.70 -1.98 -0.89 Budesonide N 2.01 93.1 -1.34 -1.19 -2.09

Aspirin A 1.70 63.6 0.16 0.33 1.30 Bupropion B 3.22 29.1 -1.16 -1.31 -0.01

Acrivastine Z 2.95 53.4 -2.00 -0.96 0.65 Buspirone B 2.21 69.6 -0.23 0.25 -1.12

Acyclovir N 0.04 119.1 0.96 0.74 0.94 Caffeine N 0.74 61.8 1.04 1.14 0.33

Albendazole A 2.20 92.3 -1.64 -1.68 -1.11 Camazepam N 3.23 62.2 -1.74 -2.14 -1.65

Alprazolam N 4.74 43.1 -1.49 -3.41 -1.20 Captopril A 0.64 96.4 0.66 0.62 1.32

Alprenolol B 2.37 41.5 -0.72 -0.28 0.96 Carbamazepine N 2.45 58.9 -1.43 -1.15 -1.15

Amantadine B 2.50 26.0 -1.07 -0.41 3.77 Carisoprodol N 0.75 90.7 -0.10 -0.64 -0.29

Ambroxol N 3.12 49.5 -1.11 -1.99 -1.79 Cefatrizine Z 1.34 225.1 -0.74 0.85 1.75

Amiloride B 0.67 159.3 0.09 -0.08 1.75 Ceftibuten Z 0.33 216.5 -1.15 0.87 4.14

Alminoprofen Z 2.58 49.3 -0.17 -0.31 2.75 Cefuroxime A -0.86 199.1 -0.55 0.06 0.90

Aminopyrine N 2.32 30.2 1.35 1.31 0.05 Celecoxib N 3.18 86.4 -2.30 -1.59 -1.88

Amisulpride B 1.20 110.1 -0.54 -0.28 0.81 Celiprolol B 1.70 90.9 -0.77 -0.96 0.31

Amitriptyline B 4.76 3.2 -2.35 -1.23 -0.30 Cephalexin Z 0.98 138.0 -0.52 0.86 2.33

Amoxicillin Z 0.58 158.3 -0.02 1.29 2.27 Cephradine Z 1.06 138.0 -0.11 0.74 2.31

Amphetamine B 2.24 26.0 0.24 0.06 2.94 Cetirizine Z 2.58 53.0 -1.18 0.20 1.22

Ampicillin Z 1.06 138.0 -0.21 0.98 2.22 Chloramphenicol N 1.23 115.4 0.39 0.15 -0.02

Amprenavir N 1.12 139.6 -1.31 -1.04 -2.35 Chloroquine B 3.52 28.2 -1.76 -1.55 0.78

Antipyrine N 2.31 26.9 1.68 0.79 0.34 Chlorothiazide A -0.22 135.5 -0.38 0.08 1.04

Artesunate A 2.64 100.5 -0.17 -0.96 -0.48 Chlorpheniramine B 3.14 16.1 -1.28 -0.19 0.39

Astemizole B 4.63 42.3 -2.92 -1.90 -3.16 Chlorpromazine B 3.77 36.4 -2.38 -2.30 -0.66

Atenolol B 0.93 84.6 -0.37 0.40 1.67 Chlorprothixene B 4.80 31.5 -3.43 -2.06 -0.98

Atorvastatin A 4.10 111.8 -3.20 -3.17 -3.88 Chlortetracycline Z -0.90 181.6 -0.55 0.68 2.30

Atropine B 2.21 49.8 0.40 -0.15 0.85 Chlorzoxazone N 1.47 46.0 0.47 -1.02 0.69

Azithromycin B 0.14 180.1 -0.29 -0.22 -1.53 Cimetidine B 0.82 114.2 -0.08 -0.08 -0.12

Baclofen Z 2.11 63.3 -0.15 -0.21 3.13 Ciprofloxacin Z 1.67 74.6 0.13 -0.80 1.97

Benazepril Z 2.54 95.9 -1.98 -1.25 0.79 Cisapride B 1.98 86.1 -1.92 -1.53 -2.20

Bendroflumethiazide N 1.58 135.1 -0.68 -0.89 -0.78 Clarithromycin B 0.04 182.9 -0.66 -0.89 -1.48

Betaxolol B 1.99 50.7 -1.53 -0.42 0.45 Clonidine B 2.66 36.4 -3.32 -1.45 0.46

Bicalutamide N 2.74 115.6 -2.03 -2.45 -1.54 Clopidogrel bisul. N 3.12 57.8 -1.93 -0.72 -1.29

Bisoprolol B 1.60 60.0 -1.15 -0.07 2.51 Clozapine B 2.48 35.2 -0.82 -1.23 -1.77

Bosentan Z 2.69 154.0 -2.04 -3.74 -2.65 Codeine B 2.17 41.9 -0.24 -0.39 0.66

Bromazepam N 2.18 54.4 -1.40 -1.52 -0.90 Colchicine N 1.37 83.1 -1.56 -0.44 -1.08

Bromocriptine B 3.06 118.2 -1.07 -1.12 -3.85 Cortisone N 1.53 91.7 -0.85 -0.68 -0.84

SI15


Drug Ionica cLogPb

cPSAc

(Å2)


(Å2)


LogS (mg/ml) LogS (mg/ml)

Cycloserine B -1.50 64.4 2.94 1.48 3.23 Etoposide N 0.13 171.8 -0.01 -1.18 -1.81

Cyclosporine A N -0.32 278.8 -2.02 -0.96 -7.99 Etoricoxib N 2.93 68.3 -2.48 -2.86 -2.00

Cymarin N 1.66 131.8 -1.09 -1.52 -1.62 Famotidine B 0.08 237.8 -0.57 -1.03 0.63

Danazol N 4.15 46.3 -1.75 -2.36 -2.05 Felodipine N 3.22 64.6 -2.15 -1.96 -2.21

Darunavir N 1.20 148.8 -1.18 -1.22 -2.40 Fenoprofen A 3.20 46.5 -1.09 -1.87 -0.48

Dasatinib B 3.27 134.8 -1.89 -2.01 -1.97 Fenoterol B 1.64 93.0 -0.80 0.50 0.20

Desipramine B 3.64 15.3 -1.40 -1.85 1.19 Fexofenadine Z 4.09 81.0 -2.58 -2.16 -0.52

Dexamethasone N 1.86 94.8 -1.30 -0.66 -0.97 Flecainide B 2.52 59.6 -1.49 -1.94 0.08

Dextromethorphan B 3.64 12.5 -2.07 -1.08 0.60 Flurbiprofen A 3.90 37.3 -1.60 -1.97 -0.31

Diazepam N 3.36 32.7 -1.91 -2.22 -1.31 Fluconazole N 3.49 81.7 0.14 0.31 0.06

Diclofenac A 3.99 49.3 -2.35 -2.17 -0.94 Fluoxetine B 3.53 21.3 -2.44 -0.72 0.85

Didanosine A 0.74 93.0 0.82 -0.40 0.93 Fluparoxan B 1.39 30.5 1.29 0.09 1.25

Diflunisal A 3.99 57.5 -1.15 -1.65 0.28 Flupenthixol B 3.89 55.0 -2.40 -1.32 -2.11

Digoxin N 0.96 203.1 -0.89 -2.79 -3.13 Flutamide N 3.16 74.9 -2.19 -1.18 -0.72

Diltiazem B 2.67 84.4 -1.77 -0.80 -1.31 Fluvastatin A 3.35 82.7 -2.36 -2.20 -1.36

Diphenhydramine B 3.26 12.5 -1.12 0.10 0.12 Folic acid A 0.57 213.3 -1.12 -0.54 0.16

Dipyridamole B 2.03 145.4 -0.04 -1.12 -1.69 Furazolidone N 0.52 100.9 -0.44 -0.82 0.44

Dicloxacillin A 3.20 138.0 -1.53 -2.11 -0.68 Furosemide A 0.43 131.0 -0.92 -0.80 0.03

Disopyramide B 2.47 59.2 -1.31 0.11 1.17 Gabapentin Z 1.15 63.3 0.64 0.43 3.95

Domperidone B 2.53 78.8 -1.03 -3.24 -2.33 Gancyclovir N -0.38 139.3 1.06 1.26 0.94

Doxycycline Z -1.39 181.6 -0.24 1.28 2.56 Gefitinib B 2.91 68.7 -1.57 -2.41 -2.35

Efavirenz N 3.34 38.3 -2.07 -3.67 -1.53 Glipizide A 0.60 138.5 -1.78 -0.80 -1.87

Emetine B 3.31 52.2 -2.55 -1.38 -1.22 Glutaminic Acid Z -2.95 100.6 1.91 1.75 6.07

Enalapril Z 1.64 95.9 -0.68 0.10 1.96 Grepafloxacin Z 2.14 74.6 -0.20 -1.49 1.59

Enalaprilat Z 1.18 106.9 -0.06 0.49 2.87 Griseofulvin N 0.98 71.1 -1.30 -1.41 -0.73

Enoxacin Z 2.05 87.5 0.04 -0.60 2.49 Guanabenz B 2.68 76.8 -1.05 -2.10 0.13

Entacapone A 1.11 130.4 -1.10 0.12 -0.52 Guanoxan B 0.51 82.9 0.08 -0.03 4.33

Erlotinib N 2.90 74.7 -2.05 -0.92 -2.52 Haloperidol B 4.01 40.5 -2.35 -2.12 -1.49

Erythromycin B -0.14 193.9 -0.34 -0.77 -1.57 Hydralazine B 1.93 63.8 0.42 -0.09 1.05

Exemestane N 3.65 34.1 -2.17 -1.48 -1.46 Hydrochlorothiazide N -0.55 135.1 0.35 -0.07 0.68

Ephedrine B 1.66 32.3 0.92 0.78 2.53 Hydrocortisone N 1.62 94.8 -0.70 -0.62 -0.93

Estradiol N 3.64 40.5 -2.67 -1.58 -1.50 Ibuprophen A 3.23 37.3 -1.17 -0.59 0.08

Ethinyl estradiol N 4.00 40.5 -2.17 -1.98 -1.69 Ibuproxam N 2.80 49.3 -1.14 -0.82 -0.18

Ethionamide B 0.83 71.0 -0.08 0.85 0.35 Imatinib B 2.91 86.3 -1.84 -1.69 -3.33

Etodolac A 2.39 58.6 -0.62 -0.55 0.31 Imipramine B 3.88 6.5 -1.18 -1.47 -0.07

SI16



(Å2)


(Å2)



Indinavir B 1.73 118.0 -1.32 -0.54 -3.84 Metformin B -0.33 91.5 0.35 1.98 5.62

Indobufen A 3.06 57.6 -1.11 -1.49 -0.69 Methadone B 4.10 20.3 -2.23 -0.36 -0.10

Indomethacin A 3.32 68.5 -2.62 -2.84 -1.41 Methotrexate Z 1.31 210.5 -0.77 -1.11 2.52

Irbesartan Z 5.11 87.1 -2.05 -1.25 -0.05 Methyldopa Z 0.49 103.8 0.35 1.27 3.65

Isoxicam A 0.82 121.1 -0.66 -1.66 -0.23 Methylprednisolone N 1.75 94.8 -0.96 -0.54 -1.12

Isradipine N 1.72 103.6 -0.64 -0.52 -1.55 Methylscopolamine B 1.66 62.3 0.98 -0.09 0.07

Ivermectin N 1.83 170.1 -2.21 -3.68 -5.33 Metoclopramide B 1.99 67.6 -0.51 0.00 0.75

Ketanserin B 2.97 75.2 -0.80 -1.71 -2.16 Metolazone N 2.13 100.9 -1.39 -2.05 -1.65

Ketoconazole B 3.00 69.1 -2.03 -0.27 -3.05 Metoprolol B 1.65 50.7 -0.40 0.33 1.11

Ketoprofen A 3.37 54.4 -1.67 -1.66 -0.41 Midazolam B 4.27 30.2 -2.01 -3.30 -1.50

Ketorolac A 2.00 59.3 -0.29 -0.21 0.05 Minoxidil B 2.33 91.2 -0.14 0.39 1.70

Ketotifen B 3.53 48.6 -2.10 -1.61 -0.65 Morphine B 1.93 52.9 1.01 -0.09 0.88

Labetalol B 2.67 95.6 -2.24 -0.42 -0.18 Nadolol B 1.36 82.0 0.35 0.12 1.59

Lamivudine N 0.02 115.7 0.44 1.01 1.09 Naproxen A 2.76 46.5 -1.29 -1.22 -0.22

Lamotrigine N 2.79 90.7 -0.31 -1.95 -0.30 Nelfinavir B 3.51 127.2 -2.72 -2.83 -4.15

Lansoprazole N 1.75 87.1 -0.60 -0.82 -1.22 Netivudine N -0.80 124.8 0.30 -0.46 0.91

Levodopa Z -2.03 103.8 0.52 1.35 3.77 Nevirapine N 2.17 63.6 -1.00 -2.24 -0.75

Levothyroxine Z 1.77 92.8 -2.05 -4.72 -0.09 Nicardipine B 3.08 113.7 -2.61 -1.30 -2.45

Lidocaine B 2.52 32.3 -0.23 0.00 -0.03 Nicotine B 1.27 16.1 1.97 1.42 1.54

Lincomycin B -0.73 147.8 1.47 1.05 0.24 Nifedipine N 2.07 110.5 -1.13 -0.70 -1.20

Lisinopril Z 1.11 133.0 -0.66 0.18 4.31 Nisoldipine N 2.77 110.5 -2.24 -1.37 -1.95

Lisuride B 1.95 51.4 -0.85 -0.21 -1.44 Nitrendipine N 2.31 110.5 -1.26 -0.96 -1.72

Lomefloxacin Z 1.79 74.6 -0.96 -1.00 1.93 Nitrofurantoin A 0.10 120.7 -0.38 -0.64 0.78

Loperamide B 4.36 43.8 -3.07 -1.13 -2.30 Nordazepam N 3.11 41.5 -1.66 -2.26 -1.26

Lopinavir N 2.91 120.0 -2.72 -3.33 -4.51 Norfloxacin Z 1.43 74.6 0.00 -0.36 2.06

Loracarbef Z 1.23 112.7 -0.48 0.12 2.01 Ofloxacin Z 1.15 75.0 0.16 -0.17 1.98

Lobucavir A 0.55 130.1 0.88 1.52 0.94 Olopatadine Z 3.07 49.8 -1.50 -0.82 1.40

Lorazepam N 3.36 61.7 -1.75 -2.74 -1.46 Olsalazine Z 1.59 139.8 -1.11 -1.06 0.28

Losartan Z 4.55 92.5 -2.34 -2.36 0.49 Omeprazole N 1.13 96.3 -0.44 -0.18 -1.36

Lovastatin N 3.80 72.8 -1.61 -1.97 -2.48 Ondansetron B 2.46 39.8 -0.60 0.46 -0.78

Loxoprofen A 2.44 54.4 -1.18 -0.77 -0.04 Orphenadrine B 3.50 12.5 -1.52 -0.22 -0.23

Mebendazole A 2.42 84.1 -1.41 -2.39 -1.70 Ouabain N -0.61 206.6 0.66 0.05 -0.31

Mefenamic acid A 3.47 49.3 -1.86 -1.51 -0.86 Oxazepam N 3.12 61.7 -1.05 -2.05 -1.09

Meloxicam Z 0.76 136.2 -0.80 -1.84 2.21 Oxprenolol B 1.83 50.7 -0.17 -0.07 1.17

Metaproterenol B 0.85 72.7 0.84 1.18 1.75 Oxaprozin A 3.39 63.3 -1.49 -1.69 -1.12

SI17



(Å2)


(Å2)



Papaverine B 2.44 49.8 -1.89 -1.70 -1.77 Repaglinide Z 3.71 78.9 -2.53 -2.35 -0.04

Paracetamol N 1.06 49.3 0.62 0.52 0.51 Reserpine B 1.76 117.8 -1.95 -1.66 -3.24

Penicillin V A 1.33 121.2 -0.35 0.69 0.10 Riboflavin N -0.82 161.6 -0.18 0.15 -0.15

Pentoxifylline N 1.36 78.9 0.71 0.27 -0.53 Rifabutin Z 2.26 205.6 -1.77 -3.67 -1.78

Pefloxacin Z 1.67 65.8 0.09 0.03 1.81 Rifampicin Z 0.57 216.7 -1.17 -2.60 -0.10

Phenazopyridine B -4.61 514.5 -0.55 -1.28 1.37 Rifapentine Z 1.22 216.7 -1.62 -3.89 -1.36

Phenobarbital A 0.78 75.3 -0.55 -0.43 -0.24 Risperidone B 3.61 64.2 -0.77 -1.71 -1.51

Phenylalanine Z -0.97 63.3 0.62 0.68 3.88 Ritonavir N 1.52 202.3 -2.90 -3.21 -4.94

Phenytoin N 1.80 58.2 -1.15 -0.74 -0.82 Rofecoxib N 1.78 94.8 -2.01 -0.06 -0.32

Pimozide B 5.11 41.0 -2.76 -3.80 -2.81 Rosuvastatin A 2.01 149.3 -1.05 -3.05 -1.03

Pindolol B 1.31 57.3 -0.07 -0.10 1.29 Roxithromycine B -0.32 216.9 -0.72 -1.47 -2.63

Pirenzepine B 1.11 74.2 -0.17 -0.26 -0.72 Salbutamol B 1.13 72.7 0.33 0.95 2.52

Piroxicam A 0.94 108.0 -0.85 0.34 2.28 Saquinavir B 1.63 166.8 -2.61 -2.83 -3.95

Pivampicillin B 2.10 153.3 -1.45 -0.37 -1.62 Scopolamine B 1.42 62.3 0.82 0.19 0.38

Pranlukast A 3.74 123.0 -2.49 -2.99 -0.75 Scutellarin A -1.26 207.4 0.26 0.24 -0.08

Practolol B 1.19 70.6 -0.31 0.11 1.53 Sildenafil B 1.51 121.8 -0.34 0.86 -1.69

Pravastatin A 2.05 124.3 -0.62 -0.92 -1.32 Simvastatin N 4.00 72.8 -1.91 -2.13 -2.55

Prazocin B 1.47 107.0 -0.39 -1.87 -1.91 Sorivudine N -0.66 124.8 1.17 1.07 0.47

Pranoprofen A 2.81 59.4 0.01 -2.21 -0.60 Sotalol B 0.71 86.8 -0.11 -0.39 2.12

Prednisolone N 1.53 94.8 -0.62 -0.40 -0.91 Sparfloxacin Z 2.00 100.6 -0.96 -1.87 1.85

Primaquine B 1.75 60.2 -1.25 -0.77 2.36 Spironolactone B 2.19 45.6 -0.48 -0.59 -0.65

Progesterone N 4.05 34.1 -2.26 -2.04 -1.95 Stavudine N 0.14 84.3 1.61 1.07 0.84

Promazine B 3.26 36.4 -1.68 -1.61 -0.04 Sulfadiazine A 0.49 106.4 -0.22 0.11 0.02

Promethazine B 3.26 36.4 -1.61 -1.72 -0.29 Sulfamethizole A 0.67 134.6 -0.21 -0.14 0.59

Propranolol B 2.53 41.5 -1.10 -1.16 1.01 Sulfamethoxazole A 0.97 106.6 -0.34 -0.62 0.12

Propylthiouracil N 0.83 80.7 -0.33 0.10 0.44 Sulfapyridine A 1.15 93.5 -0.62 -0.36 -0.21

Pyridoxine N -0.72 73.6 1.21 1.57 1.46 Sulfasalazine A 1.46 146.2 -1.78 -0.27 -0.16

Pyrimethamine B 3.05 77.8 -0.74 -2.51 -0.58 Sulfinpyrazone A 3.77 76.9 -0.49 -0.48 -0.80

Quinidine B 2.19 45.6 -0.48 -0.59 -0.86 Sulfisoxazole A 0.86 106.6 -0.51 -0.92 0.44

Raffinose N -5.50 268.7 2.83 2.68 4.98 Sulindac A 4.28 73.6 -1.60 -0.89 -1.62

Raloxifene B 3.51 98.2 -3.29 -3.19 -3.04 Sulpiride B 0.44 110.1 -0.27 0.51 0.97

Ranitidine B 0.66 111.6 -1.10 -1.03 0.71 Sumatriptan B 0.89 73.6 -0.89 -0.19 1.04

Rapamycin A 1.58 195.4 -2.76 -3.74 -6.39 Tacrolimus A 1.32 178.4 -2.40 -2.77 -5.00

Rebamipide A 2.88 99.3 -1.99 -1.37 -1.16 Talinolol B 1.88 82.6 -1.35 -1.61 -0.21

Remikiren B 2.22 169.9 -1.67 -2.29 -2.72 Tamoxifen B 5.20 12.5 -2.99 -1.83 -2.09

SI18



(Å2)


(Å2)



Telithromycin Z 1.08 171.9 -1.55 -1.59 -0.53 Tramadol B 2.32 32.7 -0.12 0.24 1.19

Telmisartan Z 5.70 72.9 -2.46 -3.09 -2.12 Tranexamic acid Z 0.83 63.32 1.26 0.68 3.92

Tenidap A 2.59 113.6 -1.57 -3.09 -1.35 Trazodone B 3.53 45.78 -0.54 -0.66 -2.55

Tenoxicam Z 0.50 136.2 -0.55 -1.41 2.13 Triazolam N 4.97 43.07 -1.74 -3.10 -1.67

Terazosin B 1.40 103.0 0.18 -0.70 -1.23 Trifluoperazine B 3.55 39.65 -2.06 -1.80 -1.69

Terbinafine B 4.98 3.2 -3.13 -3.68 -2.51 Trimethoprim B 1.26 105.51 -0.21 -0.85 0.02

Terbutaline B 1.13 72.7 0.77 1.10 1.55 Trovafloxacin Z 3.21 101.45 -1.15 -3.41 1.04

Terfenadine B 4.94 43.7 -3.34 -2.71 -3.22 Valacyclovir B 0.76 151.14 0.55 0.11 0.78

Testosterone N 3.70 37.3 -1.48 -1.60 -1.47 Valproic acid A 2.06 37.3 0.37 0.19 0.71

Tetracycline Z -0.88 181.6 0.12 0.82 2.79 Valsartan A 4.15 112.07 -1.64 -3.54 -2.16

Thalidomide A 0.74 85.2 0.41 0.27 -0.13 Verapamil B 3.23 63.95 -2.40 -1.87 -1.39

Theophylline N 0.40 72.7 1.36 0.78 0.37 Viloxazine B 1.01 39.72 0.09 0.49 1.20

Tiacrilast A 2.03 97.5 -0.89 -0.54 0.66 Warfarin A 3.20 67.51 -1.33 -1.23 -0.80

Tiaprofenic Acid A 2.55 82.6 -1.49 -1.77 0.00 Xamoterol B -0.57 103.29 0.54 1.59 0.72

Timolol B 1.22 108.0 -0.57 1.03 1.17 Yohimbine B 2.25 65.56 -0.46 -0.51 -0.63

Tinidazole N 1.00 106.2 0.48 1.63 0.54 Zaltoprofen A 3.49 79.67 -1.86 -2.01 -0.81

Tolbutamide A 1.44 83.7 -0.70 -0.39 -0.43 Zidovudine N -0.57 133.08 1.21 0.98 0.41

Tolcapone A 2.40 103.4 1.71 1.51 -0.60 Ziprasidone B 3.44 76.71 -2.14 -1.27 -2.18

Tolmetin A 2.00 59.3 -0.89 -0.37 0.13 Zolmitriptan B 1.09 57.36 -0.72 -0.12 1.07

Topiramate N -0.26 123.9 0.83 0.83 0.64 Zolpidem N 3.03 37.61 -1.50 -2.51 -1.72

Topotecan Z 1.57 104.9 -0.07 0.67 1.56 Zomepirac A 2.52 59.3 -1.59 -1.04 -0.26

aIonization state: Acid (A), Base (B), Neutral (N), Zwitterions (Z) according to ACD/Labs program criteria.

239

bPartition coefficient calculated by Moriguchi model (MLOGP descriptor implemented in Dragon software).

240-242

cCalculated topological Polar Surface Area by the summation of surface contributions of polar fragments with nitrogen and oxygen plus “slightly polar” fragments

containing phosphorus and sulfur (a descriptor of Dragon software).243

dAqueous solubility computed by ALOGPS v.2.1.

244

eMinimum solubility between pH range of 2-8 computed by ACD/Labs v.3.0 (Advanced Chemistry Development: Toronto, Canada,

http://www.acdlabs.com/products/pc_admet/physchem/physchemsuite/) fMinimum solubility between pH range of 3-8 computed by Volsurf + v.1.0.4.

245

http://www.acdlabs.com/products/pc_admet/physchem/physchemsuite/

SI19

REFERENCE

1. Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines

immediate-release, solid oral dosage forms; Technical Report Series No. 937; 40th; WHO Expert Committee on

Specification for Pharmaceutical Preparations, WHO Technical Report Series, No. 937, 2006; pp 391-461. At:

http://www.who.int/medicines/publications/essentialmedicines/en/index.html. Accessed 3 March 2012

2. Kasim, N. A.; Whitehouse, M.; Ramachandran, C.; Bermejo Sanz, M.; Lennernas, H.; Hussain, A. S.; Junginger,

H. E.; Stavchansky, S. A.; Midha, K. K.; Shah, V. P.; Amidon, G. Molecular Properties of WHO Essential Drugs and

Provisional Biopharmaceutical Classification. Mol. Pharmaceutics 2004, 1 (1), 85-96.

3. Takagi, T.; Ramachandran, S.; Bermejo, M.; Yamashita, S.; Yu, L. X.; Amidon, G. L. A Provisional

Biopharmaceutical Classification of the Top 200 Oral Drug Products in the United States, Great Britain, Spain, and

Japan. Mol. Pharmaceutics 2006, 3 (6), 631-643.

4. Lindenberg, M.; Kopp, S.; Dressman, J. B. Classification of orally administered drugs on the World Health

Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur. J. Pharm.

Biopharm. 2004, 58 (2), 265-278.

5. Custodio, J. M.; Wu, C. Y.; Benet, L. Z. Predicting drug disposition, absorption/elimination/transporter interplay

and the role of food on drug absorption. Adv. Drug Deliv. Rev. 2008, 60 (6), 717-733.

6. Benet, L. Z.; Broccatelli, F.; Oprea, T. I. BDDCS Applied to Over 900 Drugs. AAPS J. 2011, 13 (4), 519-547.

7. Liang, E.; Chessic, K.; Yazdanian, M. Evaluation of an accelerated Caco-2 cell permeability model. J. Pharm.

Sci. 2000, 89 (3), 336-345.

8. Yamashita, F.; Fujiwara, S.; Hashida, M. The "latent membrane permeability" concept: QSPR analysis of

inter/intralaboratory variable Caco-2 permeability. J. Chem. Inf. Comput. Sci. 2002, 42 (2), 408-413.

9. Marrero-Ponce, Y.; Cabrera, M. A.; Romero, V.; Bermejo, M.; Siverio, D.; Torrens, F. Prediction of Intestinal

Epithelial Transport of Drug in (Caco-2) Cell Culture from Molecular Structure using in silico Approaches During Early

Drug Discovery. Internet Electron. J. Mol. Des. 2005, 4 (2), 124-150.

10. Hou, T. J.; Zhang, W.; Xia, K.; Qiao, X. B.; Xu, X. J. ADME Evaluation in Drug Discovery. 5. Correlation of

Caco-2 Permeation with Simple Molecular Properties. J. Chem. Inf. Comput. Sci. 2004, 44, 1585-1600.

11. Nordqvist, A.; Nilsson, J.; Lindmark, T.; Eriksson, A.; Garberg, P.; Kihlen, M. A General Model for Prediction of

Caco-2 Cell Permeability. QSAR Comb. Sci. 2004, 23, 303-310.

12. Usansky, H. H.; Sinko, P. J. Estimating human drug oral absorption kinetics from Caco-2 permeability using an

absorption-disposition model: model development and evaluation and derivation of analytical solutions for k(a) and F(a).

J. Pharmacol. Exp. Ther. 2005, 314 (1), 391-399.

13. Thomas, S.; Brightman, F.; Gill, H.; Lee, S.; Pufong, B. Simulation modelling of human intestinal absorption

using Caco-2 permeability and kinetic solubility data for early drug discovery. J. Pharm. Sci. 2008, 97 (10), 4557-4574.

14. Irvine, J. D.; Takahashi, L.; Lockhart, K.; Cheong, J.; Tolan, J. W.; Selick, H. E.; Grove, J. R. MDCK (Madin-

Darby canine kidney) cells: A tool for membrane permeability screening. J. Pharm. Sci. 1999, 88 (1), 28-33.

15. Subramanian, G.; Kitchen, D. B. Computational approaches for modeling human intestinal absorption and

permeability. J. Mol. Model. 2006, 12 (5), 577-589.

16. Skolnik, S.; Lin, X.; Wang, J.; Chen, X. H.; He, T.; Zhang, B. Towards prediction of in vivo intestinal absorption

using a 96-well Caco-2 assay. J. Pharm. Sci. 2010, 99 (7), 3246-3265.

17. Lin, X.; Skolnik, S.; Chen, X.; Wang, J. Attenuation of Intestinal Absorption by Major Efflux Transporters:

Quantitative Tools and Strategies Using a Caco-2 Model. Drug metab. Dispos. 2011, 39 (2), 265-274.

18. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 9th ed.; Goodman, L. S.; Limbird, L. E.;

Milinoff, P. B.; Ruddon, R. W.; Gilman, A. G., Eds. Mcgraw-Hill (Tx): New York, USA, 1996; p 1905.

19. Hou, T.; Wang, J.; Li, Y. ADME evaluation in drug discovery. 8. The prediction of human intestinal absorption

by a support vector machine. J. Chem. Inf. Model. 2007, 47 (6), 2408-2415.

20. Varma, M. V.; Obach, R. S.; Rotter, C.; Miller, H. R.; Chang, G.; Steyn, S. J.; El-Kattan, A.; Troutman, M. D.

Physicochemical space for optimum oral bioavailability: contribution of human intestinal absorption and first-pass

elimination. J. Med. Chem. 2010, 53 (3), 1098-1108.

21. Yalkowsky, S. H.; Johnson, J. L.; Sanghvi, T.; Machatha, S. G. A 'Rule of Unity' for Human Intestinal

Absorption. Pharm. Res. 2006, 23 (10), 2475-2481.

22. Gozalbes, R.; Jacewicz, M.; Annand, R.; Tsaioun, K.; Pineda-Lucena, A. QSAR-based permeability model for

drug-like compounds. Bioorg. Med. Chem. 2011, 19, 2615–2624.

23. Jung, S. J.; Choi, S. O.; Um, S. Y.; Kim, J. I.; Choo, H. Y.; Choi, S. Y.; Chung, S. Y. Prediction of the

permeability of drugs through study on quantitative structure-permeability relationship. J. Pharm. Biomed. Anal. 2006,

41 (2), 469-475.

24. Yee, S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in

man--fact or myth. Pharm. Res. 1997, 14 (6), 763-766.

http://www.who.int/medicines/publications/essentialmedicines/en/index.html

SI20

25. Yazdanian, M.; Glynn, S. L.; Wright, J. L.; Hawi, A. Correlating partitioning and caco-2 cell permeability of

structurally diverse small molecular weight compounds. Pharm. Res. 1998, 15 (9), 1490-1494.

26. Yazdanian, M.; Briggs, K.; Jankovsky, C.; Hawi, A. The "high solubility" definition of the current FDA

Guidance on Biopharmaceutical Classification System may be too strict for acidic drugs. Pharm. Res. 2004, 21 (2), 293-

299.

27. Faassen, F.; Vogel, G.; Spanings, H.; Vromans, H. Caco-2 permeability, P-glycoprotein transport ratios and brain

penetration of heterocyclic drugs. Int. J. Pharm. 2003, 263 (1-2), 113-122.

28. Niwa, T. Using general regression and probabilistic neural networks to predict human intestinal absorption with

topological descriptors derived from two-dimensional chemical structures. J. Chem. Inf. Comput. Sci. 2003, 43 (1), 113-

119.

29. Wessel, M. D.; Jurs, P. C.; Tolan, J. W.; Muskal, S. M. Prediction of human intestinal absorption of drug

compounds from molecular structure. J. Chem. Inf. Comput. Sci. 1998, 38 (4), 726-735.

30. Rege, B. D.; Yu, L. X.; Hussain, A. S.; Polli, J. E. Effect of common excipients on Caco-2 transport of low-

permeability drugs. J. Pharm. Sci. 2001, 90 (11), 1776-1786.

31. Masungi, C.; Borremans, C.; Willems, B.; Mensch, J.; Van Dijck, A.; Augustijns, P.; Brewster, M. E.; Noppe, M.

Usefulness of a novel Caco-2 cell perfusion system. I. In vitro prediction of the absorption potential of passively diffused

compounds. J. Pharm. Sci. 2004, 93 (10), 2507-2521.

32. Matsson, P.; Bergstrom, C. A.; Nagahara, N.; Tavelin, S.; Norinder, U.; Artursson, P. Exploring the Role of

Different Drug Transport Routes in Permeability Screening. J. Med. Chem. 2005, 48 (2), 604-613.

33. Tavelin, S.; Taipalensuu, J.; Soderberg, L.; Morrison, R.; Chong, S.; Artursson, P. Prediction of the oral

absorption of low-permeability drugs using small intestine-like 2/4/A1 cell monolayers. Pharm. Res. 2003, 20 (3), 397-

405.

34. Furubayashi, T.; Kamaguchi, A.; Kawaharada, K.; Masaoka, Y.; Kataoka, M.; Yamashita, S.; Higashi, Y.;

Sakane, T. Kinetic Model to Predict the Absorption of Nasally Applied Drugs from in Vitro Transcellular Permeability

of Drugs. Biol. Pharm. Bull. 2007, 30 (5), 1007-1010.

35. Bergstrom, C. A.; Strafford, M.; Lazorova, L.; Avdeef, A.; Luthman, K.; Artursson, P. Absorption classification

of oral drugs based on molecular surface properties. J. Med. Chem. 2003, 46 (4), 558-570.

36. Han, H.-K.; Oh, D.-M.; Amidon, G. L. Cellular Uptake Mechanism of Amino Acid Ester Prodrugs in Caco-

2/hPEPT1 Cells Overexpressing a Human Peptide Transporter. Pharm. Res. 1998, 15 (9), 1382-1386.

37. Paixao, P.; Gouveia, L. F.; Morais, J. A. Prediction of the human oral bioavailability by using in vitro and in

silico drug related parameters in a physiologically based absorption model. Int. J. Pharm. 2012, 429 (1-2), 84-98.

38. Sugano, K. Fraction of a dose absorbed estimation for structurally diverse low solubility compounds. Int. J.

Pharm. 2011, 405 (1-2), 79-89.

39. Hämäläinen, M. D.; Frostell-Karlsson, A. Predicting the intestinal absorption potential of hits and leads. Drug

Discov Today:Technologies 2004, 1 (4), 397-405.

40. Rivera, J. C.; Yépez-Mulia, L.; Hernández-Campos, A.; Moreno-Esparza, R.; Castillo, R.; Navarrete-Vázquez, G.;

Fuentes-Noriega, I.; Jung-Cook, H. Biopharmaceutic evaluation of novel anthelmintic (1H-benzimidazol-5(6)-

yl)carboxamide derivatives. Int. J. Pharm. 2007, 343, 159–165.

41. Kataoka, M.; Masaoka, Y.; Yamazaki, Y.; Sakane, T.; Sezaki, H.; Yamashita, S. In vitro system to evaluate oral

absorption of poorly water-soluble drugs: simultaneous analysis on dissolution and permeation of drugs. Pharm Res

2003, 20 (10), 1674-1680.

42. Sugano, K. Computational oral absorption simulation of free base drugs. Int. J. Pharm. 2010, 398 (1-2), 73-82.

43. Gertz, M.; Harrison, A.; Houston, J. B.; Galetin, A. Prediction of human intestinal first-pass metabolism of 25

CYP3A substrates from in vitro clearance and permeability data. Drug Metab. Dispos. 2010, 38 (7), 1147-1158.

44. Li, C.; Liu, T.; Cui, X.; Uss, A. S.; Cheng, K. C. Development of in vitro pharmacokinetic screens using Caco-2,

human hepatocyte, and Caco-2/human hepatocyte hybrid systems for the prediction of oral bioavailability in humans. J.

Biomol. Screen. 2007, 12 (8), 1084-1091.

45. Yamashita, S.; Furubayashi, T.; Kataoka, M.; Sakane, T.; Sezaki, H.; Tokuda, H. Optimized conditions for

prediction of intestinal drug permeability using Caco-2 cells. Eur. J. Pharm. Sci. 2000, 10 (3), 195-204.

46. Kulkarni, A.; Han, Y.; Hopfinger, A. J. Predicting Caco-2 cell permeation coefficients of organic molecules using

membrane-interaction QSAR analysis. J. Chem. Inf. Comput. Sci. 2002, 42 (2), 331-342.

47. Stenberg, P.; Norinder, U.; Luthman, K.; Artursson, P. Experimental and computational screening models for the

prediction of intestinal drug absorption. J. Med. Chem. 2001, 44 (12), 1927-1937.

48. Palm, K.; Luthman, K.; Ungell, A. L.; Strandlund, G.; Artursson, P. Correlation of drug absorption with

molecular surface properties. J. Pharm. Sci. 1996, 85 (1), 32-39.

49. Lapenna, S.; Dinan, L.; Friz, J.; Hopfinger, A. J.; Liu, J.; Hormann, R. E. Semi-synthetic ecdysteroids as gene-

switch actuators: synthesis, structure-activity relationships, and prospective ADME properties. ChemMedChem 2009, 4

(1), 55-68.

SI21

50. Balimane, P. V.; Chong, S., Evaluation of Permeability and P-glycoprotein Interactions: Industry Outlook. In

Biopharmaceutics Applications in Drug Development, Krishma, R.; Yu, L., Eds. Springer: 233 Spring Street, New York,

NY 10013, USA, 2007; pp 101-138.

51. Skold, C.; Winiwarter, S.; Wernevik, J.; Bergstrom, F.; Engstrom, L.; Allen, R.; Box, K.; Comer, J.; Mole, J.;

Hallberg, A.; Lennernas, H.; Lundstedt, T.; Ungell, A. L.; Karlen, A. Presentation of a structurally diverse and

commercially available drug data set for correlation and benchmarking studies. J. Med. Chem. 2006, 49 (23), 6660-6671.

52. Stetinová, V.; Smetanová, L.; Kholová, D.; Svoboda, Z.; Kvetina, J. Transepithelial transport of ambroxol

hydrochloride across human intestinal Caco-2 cell monolayers. Gen. Physiol. Biophys. 2009, 28 (3), 309-315.

53. Aungst, B. J.; Nguyen, N. H.; Bulgarelli, J. P.; Oates-Lenz, K. The influence of donor and reservoir additives on

Caco-2 permeability and secretory transport of HIV protease inhibitors and other lipophilic compounds. Pharm Res

2000, 17 (10), 1175-1180.

54. Fossati, L.; Dechaume, R.; Hardillier, E.; Chevillon, D.; Prevost, C.; Bolze, S.; Maubon, N. Use of simulated

intestinal fluid for Caco-2 permeability assay of lipophilic drugs. Int. J. Pharm. 2008, 360 (1-2), 148-155.

55. Paixao, P.; Gouveia, L. F.; Morais, J. A. Prediction of the in vitro permeability determined in Caco-2 cells by

using artificial neural networks. Eur. J. Pharm. Sci. 2010, 41 (1), 107-117.

56. Kerns, E. H.; Di, L.; Petusky, S.; Farris, M.; Ley, R.; Jupp, P. Combined application of parallel artificial

membrane permeability assay and Caco-2 permeability assays in drug discovery. J. Pharm. Sci. 2004, 93 (6), 1440-1453.

57. Crowe, A.; Diep, S. pH dependent efflux of methamphetamine derivaties and their reversal through human Caco-

2 cell monolayers. Eur. J. Pharmacol. 2008, 592, 7-12.

58. Castillo-Garit, J. A.; Marrero-Ponce, Y.; Torrens, F.; Garcia-Domenech, R. Estimation of ADME properties in

drug discovery: predicting Caco-2 cell permeability using atom-based stochastic and non-stochastic linear indices. J.

Pharm. Sci. 2008, 97 (5), 1946-1976.

59. Biganzoli, E.; Cavenaghi, L. A.; Rossi, R.; Brunati, M. C.; Nolli, M. L. Use of a Caco-2 cell culture model for the

characterization of intestinal absorption of antibiotics. Farmaco 1999, 54 (9), 594-599.

60. He, X.; Sugawara, M.; Takekuma, Y.; Miyazaki, K. Absorption of ester prodrugs in Caco-2 and rat intestine

models. Antimicrob. Agents Chemother. 2004, 48 (7), 2604-2609.

61. Aungst, B. J.; Nguyen, N. H.; Taylor, N. J.; Bindra, D. S. Formulation and food effects on the oral absorption of a

poorly water soluble, highly permeable antiretroviral agent. J Pharm Sci 2002, 91 (6), 1390-1395.

62. Yu, L.; Bridgers, A.; Polli, J.; Vickers, A.; Long, S.; Roy, A.; Winnike, R.; Coffin, M. Vitamin E-TPGS increases

absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability. Pharm. Res. 1999, 16 (12),

1812-1817.

63. Varma, M. V.; Sateesh, K.; Panchagnula, R. Functional Role of P-Glycoprotein in Limiting Intestinal Absorption

of Drugs: Contribution of Passive Permeability to P-Glycoprotein Mediated Efflux Transport. Mol. Pharmaceutics 2005,

2 (1), 12-21.

64. Hilgendorf, C.; Spahn-Langguth, H.; Regardh, C. G.; Lipka, E.; Amidon, G. L.; Langguth, P. Caco-2 versus

Caco-2/HT29-MTX co-cultured cell lines: permeabilities via diffusion, inside- and outside-directed carrier-mediated

transport. J. Pharm. Sci. 2000, 89 (1), 63-75.

65. Saitoh, R.; Sugano, K.; Takata, N.; Tachibana, T.; Higashida, A.; Nabuchi, Y.; Aso, Y. Correction of

permeability with pore radius of tight junctions in Caco-2 monolayers improves the prediction of the dose fraction of

hydrophilic drugs absorbed by humans. Pharm Res 2004, 21 (5), 749-755.

66. Wanchana, S.; Yamashita, F.; Hashida, M. Quantitative structure/property relationship analysis on aqueous

solubility using genetic algorithm-combined partial least squares method. Pharmazie 2002, 57 (2), 127-129.

67. Du-Cuny, L.; Song, Z.; Moses, S.; Powis, G.; Mash, E. A.; Meuillet, E. J.; Zhang, S. Computational modeling of

novel inhibitors targeting the Akt pleckstrin homology domain. Bioorg Med Chem 2009, 17 (19), 6983-6992.

68. Augustijns, P.; D'Hulst, A.; Van Daele, J.; Kinget, R. Transport of Artemisinin and Sodium Artesunate in Caco-2

Intestinal Epithelial Cells. J. Pharm. Sci. 1996, 85 (6), 577-579.

69. Crivori, P.; Reinach, B.; Pezzetta, D.; Poggesi, I. Computational models for identifying potential P-glycoprotein

substrates and inhibitors. Mol. Pharmaceutics 2006, 3 (1), 33-44.

70. Pham The, H.; Gonzalez Diaz, I.; Bermejo Sanz, M.; Mangas Sanjuan, V.; Centelles, I.; Garriges, T. M.; Cabrera

Perez, M. A. In Silico Prediction of Caco-2 Permeability by a Classification QSAR Approach. Mol. Inf. 2011, 30 (4),

376-385.

71. Larger, P.; Altamura, M.; Catalioto, R. M.; Giuliani, S.; Maggi, C. A.; Valenti, C.; Triolo, A. Simultaneous LC-

MS/MS determination of reference pharmaceuticals as a method for the characterization of the Caco-2 cell monolayer

absorption properties. Anal Chem 2002, 74 (20), 5273-5281.

72. Palm, K.; Luthman, K.; Ungell, A. L.; Strandlund, G.; Beigi, F.; Lundahl, P.; Artursson, P. Evaluation of

dynamic polar molecular surface area as predictor of drug absorption: comparison with other computational and

experimental predictors. J Med Chem 1998, 41 (27), 5382-5392.

SI22

73. Ingels, F.; Beck, B.; Oth, M.; Augustijns, P. Effect of simulated intestinal fluid on drug permeability estimation

across Caco-2 monolayers. Int J Pharm 2004, 274 (1-2), 221-232.

74. Wu, Q.; Yang, X. W. The constituents of Cibotium barometz and their permeability in the human Caco-2

monolayer cell model. J. Ethnopharmacol. 2009, 125 (3), 417-422.

75. Song, J. S.; Rho, H. J.; Park, J. S.; Kim, M. S.; Lee, B. H.; Seo, J.-W.; Jeong, D. J.; Cheong, H. G.; Ahn, S. H.;

Kwon, K.-i.; Bae, M. A. Preclinical pharmacokinetics of PDE-310, a novel PDE4 inhibitor. Drug Metab Pharmacokinet

2010, DOI: 10.2133/dmpk.DMPK-10-RG-065.

76. Tannergren, C.; Bergendal, A.; Lennernas, H.; Abrahamsson, B. Toward an Increased Understanding of the

Barriers to Colonic Drug Absorption in Humans: Implications for Early Controlled Release Candidate Assessment. Mol.

Pharmaceutics 2009, 6 (1), 60-73.

77. Wu, X.; Whitfield, L. R.; Stewart, B. H. Atorvastatin transport in the Caco-2 cell model: contributions of P-

glycoprotein and the proton-monocarboxylic acid co-transporter. Pharm Res 2000, 17 (2), 209-215.

78. Foulds, G.; Shepard, R. M.; Johnson, R. B. The pharmacokinetics of azithromycin in human serum and tissues. J.

Antimicrob. Chemother. 1990, 25 (Suppl A), 73-82.

79. Hakkarainen, J. J.; Jalkanen, A. J.; Kääriäinen, T. M.; Keski-Rahkonen, P.; Venäläinen, T.; Hokkanen, J.;

Mönkkönen, J.; Suhonen, M.; Forsberg, M. M. Comparison of in vitro cell models in predicting in vivo brain entry of

drugs. Int. J. Pharm. 2010, 402, 27–36.

80. Colabufo, N. A.; Pagliarulo, V.; Berardi, F.; Contino, M.; Inglese, C.; Niso, M.; Ancona, P.; Albo, G.; Pagliarulo,

A.; Perrone, R. Bicalutamide failure in prostate cancer treatment: Involvement of Multi Drug Resistance proteins. Eur. J.

Pharmacol. 2008, 601, 38-42.

81. Haslam, I. S.; O’Reilly, D. A.; Sherlock, D. J.; Kauser, A.; Womack, C.; Coleman, T. Pancreatoduodenectomy as

a source of human small intestine for Ussing chamber investigations and comparative studies with rat tissue. Biopharm.

Drug Dispos. 2011, 32 (4), 210–221.

82. Guangli, M.; Yiyu, C. Predicting Caco-2 permeability using support vector machine and chemistry development

kit. J Pharm Pharm Sci 2006, 9 (2), 210-221.

83. Zhao, Y. H.; Le, J.; Abraham, M. H.; Hersey, A.; Eddershaw, P. J.; Luscombe, C. N.; Butina, D.; Beck, G.;

Sherborne, B.; Cooper, I.; Platts, J. A. Evaluation of human intestinal absorption data and subsequent derivation of a

quantitative structure-activity relationship (QSAR) with the Abraham descriptors. J. Pharm. Sci. 2001, 90 (6), 749-784.

84. Yamashita, F.; Wanchana, S.; Hashida, M. Quantitative structure/property relationship analysis of Caco-2

permeability using a genetic algorithm-based partial least squares method. J. Pharm. Sci. 2002, 91 (10), 2230-2239.

85. Jia, L.; Wong, H. In vitro and in vivo assessment of cellular permeability and pharmacodynamics of S-

nitrosylated Captopril, a nitric oxide donor. Br J Pharmacol 2001, 134, 1697-1704.

86. Mandagere, A. K.; Thompson, T. N.; Hwang, K. K. Graphical model for estimating oral bioavailability of drugs

in humans and other species from their Caco-2 permeability and in vitro liver enzyme metabolic stability rates. J Med

Chem 2002, 45 (2), 304-311.

87. Shimizu, R.; Sukegawa, T.; Tsuda, Y.; Itoh, T. Quantitative prediction of oral absorption of PEPT1 substrates

based on in vitro uptake into Caco-2 cells. Int J Pharm 2008, 354 (1-2), 104-110.

88. Emami, J.; Fallah, R.; Ajami, A. A rapid and sensitive HPLC method for the analysis of celecoxib in human

plasma: application to pharmacokinetic studies. DARU 2008, 16 (4), 211-217.

89. Karlsson, J.; Kuo, S. M.; Ziemniak, J.; Artursson, P. Transport of celiprolol across human intestinal epithelial

(Caco-2) cells: mediation of secretion by multiple transporters including P-glycoprotein. Br J Pharmacol 1993, 110 (3),

1009-1016.

90. Huang, J. G.; Si, L. Q.; Zuo, K. Y.; Wu, X. G.; Qiu, J.; Li, G. The inhibitory effect of pluronic on P-glycoprotein

drug pump. Yao Xue Xue Bao 2007, 42 (9), 989-994.

91. Yamashita, S.; Konishi, K.; Yamazaki, Y.; Taki, Y.; Sakane, T.; Sezaki, H.; Furuyama, Y. New and better

protocols for a short-term Caco-2 cell culture system. J Pharm Sci 2002, 91 (3), 669-679.

92. Marrero-Ponce, Y.; Cabrera, M. A.; Romero, V.; Ofori, E.; Montero, L. A. Total and Local Quadratic Indices of

the "Molecular Pseudograph´s Atom Adjacency Matrix". Application to Prediction of Caco-2 Permeability of Drugs. Int.

J. Mol. Sci. 2003, 4, 512-536.

93. Miret, S.; Abrahamse, L.; de Groene, E. M. Comparison of in vitro models for the prediction of compound

absorption across the human intestinal mucosa. J Biomol Screen 2004, 9 (7), 598-606.

94. Wanchana, S.; Yamashita, F.; Hara, H.; Fujiwara, S.; Akamatsu, M.; Hashida, M. Two- and three-dimensional

QSAR of carrier-mediated transport of beta-lactam antibiotics in Caco-2 cells. J Pharm Sci 2004, 93 (12), 3057-3065.

95. Behrens, I.; Kissel, T. Do cell culture conditions influence the carrier-mediated transport of peptides in Caco-2

cell monolayers? Eur. J. Pharm. Sci. 2003, 19 (5), 433-442.

96. Schwinghammer, T. L.; Norden, G. W.; Gill, E. Pharmcokinetics of cephradine administered intravenously and

orally to young and elderly subjects. J. Clin. Pharmacol. 1990, 30, 893-899.

SI23

97. Tam, K. Y.; Avdeef, A.; Tsinman, O.; Sun, N. The Permeation of Amphoteric Drugs through Artificial

Membranes - An in Combo Absorption Model Based on Paracellular and Transmembrane Permeability. J. Med. Chem.

2010, 53 (1), 392-401.

98. Velicky, M.; Tam, K. Y.; Dryfe, R. A. W. In situ artificial membrane permeation assay under hydrodynamic

control: Correlation between drug in vitro permeability and fraction absorbed in humans. Eur. J. Pharm. Sci. 2011, 44

(3), 299-309.

99. Thanou, M.; Florea, B. I.; Langemeyer, M. W.; Verhoef, J. C.; Junginger, H. E. N-trimethylated chitosan chloride

(TMC) improves the intestinal permeation of the peptide drug buserelin in vitro (Caco-2 cells) and in vivo (rats). Pharm

Res 2000, 17 (1), 27-31.

100. Pade, V.; Stavchansky, S. Link between drug absorption solubility and permeability measurements in Caco-2

cells. J. Pharm. Sci. 1998, 87 (12), 1604-1607.

101. Wang, Z.; Hop, C. E.; Leung, K. H.; Pang, J. Determination of in vitro permeability of drug candidates through a

caco-2 cell monolayer by liquid chromatography/tandem mass spectrometry. J. Mass. Spectrom. 2000, 35 (1), 71-76.

102. Lentz, K. A.; Hayashi, J.; Lucisano, L. J.; Polli, J. E. Development of a more rapid, reduced serum culture system

for Caco-2 monolayers and application to the biopharmaceutics classification system. Int J Pharm 2000, 200 (1), 41-51.

103. Suenderhauf, C.; Hammann, F.; Maunz, A.; Helma, C.; Huwyler, J. Combinatorial QSAR Modeling of Human

Intestinal Absorption. Mol. Pharmaceutics 2010, 8 (1), 213–224.

104. Saha, P.; Kou, J. H. Effect of bovine serum albumin on drug permeability estimation across Caco-2 monolayers.

Eur J Pharm Biopharm 2002, 54 (3), 319-324.

105. Balimane, P. V.; Han, Y.-H.; Chong, S. Current Industrial Practices of Assessing Permeability and P-

Glycoprotein Interaction. AAPS J 2006, 8 (1), E1-E13.

106. Ruiz-Garcia, A.; Lin, H.; Pla-Delfina, J. M.; Hu, M. Kinetic characterization of secretory transport of a new

ciprofloxacin derivative (CNV97100) across Caco-2 cell monolayers. J Pharm Sci 2002, 91 (12), 2511-2519.

107. Rodriguez-Ibanez, M.; Nalda-Molina, R.; Montalar-Montero, M.; Bermejo, M. V.; Merino, V.; Garrigues, T. M.

Transintestinal secretion of ciprofloxacin, grepafloxacin and sparfloxacin: in vitro and in situ inhibition studies. Eur. J.

Pharm. Biopharm. 2003, 55 (2), 241-246.

108. Taubert, D.; von Beckerath, N.; Grimberg, G.; Lazar, A.; Jung, N.; Goeser, T.; Kastrati, A.; Schömig, A.;

Schömig, E. Impact of P-glycoprotein on clopidogrel absorption. Clin. Pharmacol. Ther. 2006, 80 (5), 486-501.

109. Tirtha, P. V.; Jigna, S. S.; Patel, C. N. Ticagrelor Versus Clopidogrel in Acute Coronary Syndromes.

International Journal of Pharmaceutical and Chemical Sciences 2012, 1 (1), 447-454.

110. Zhu, C.; Jiang, L.; Chen, T. M.; Hwang, K. K. A comparative study of artificial membrane permeability assay for

high throughput profiling of drug absorption potential. Eur. J. Med. Chem. 2002, 37 (5), 399-407.

111. Lau, Y. Y.; Chen, Y. H.; Liu, T. T.; Li, C.; Cui, X.; White, R. E.; Cheng, K. C. Evaluation of a Novel In Vitro

Caco-2 Hepatocyte Hybrid System for Ppredicting In Vivo Oral Biovailability. Drug Metab Dispos 2004, 9 (32), 937-

942.

112. Heikkinen, A. T.; Baneyx, G.; Caruso, A.; Parrott, N. Application of PBPK modeling to predict human intestinal

metabolism of CYP3A substrates – An evaluation and case study using GastroPlus™. Eur. J. Pharm. Sci. 2012, 47 (2),

375-386.

113. Takano, R.; Sugano, K.; Higashida, A.; Hayashi, Y.; Machida, M.; Aso, Y.; Yamashita, S. Oral absorption of

poorly water-soluble drugs: computer simulation of fraction absorbed in humans from a miniscale dissolution test.

Pharm. Res. 2006, 23 (6), 1144-1156.

114. Charman, W. N.; Rogge, M. C.; Boddy, A. W.; Berger, B. M. Effect of food and a monoglyceride emulsion

formulation on danazol bioavailability. J. Clin. Pharmacol. 1993, 33 (4), 381-386.

115. Fagerholm, U. Evaluation and suggested improvements of the Biopharmaceutics Classification System (BCS). J

Pharm Pharmacol 2007, 59 (6), 751-757.

116. Berginc, K.; Trdan, T.; Trontelj, J.; Kristl, A. HIV Protease Inhibitors: Garlic Supplements and First-pass

Intestinal Metabolism Impact on the Therapeutic Efficacy. Biopharm. Drug Dispos. 2010, 31, 495–505.

117. Stappaerts, J.; Annaert, P.; Augustijns, P. Site dependent intestinal absorption of darunavir and its interaction

with ketoconazole. Eur. J. Pharm. Sci. 2013, http://dx.doi.org/10.1016/j.ejps.2013.01.015.

118. Vermeir, M.; Lachau-Durand, S.; Mannens, G.; Cuyckens, F.; van Hoof, B.; Raoof, A. Absorption, Metabolism,

and Excretion of Darunavir, a New Protease Inhibitor, Administered Alone and with Low-Dose Ritonavir in Healthy

Subjects Drug Metab. Dispos. 2009, 37 (4), 809-820.

119. Kanaan, M.; Daali, Y.; Dayer, P.; Desmeules, J. Lack of dextromethorphan interaction with P-glycoprotein. Clin.

Pharmacol. Ther. 2005, 77, P10.

120. Sjöberg, Å.; Lutz, M.; Tannergren, C.; Wingolf, C.; Borde, A.; Ungell, A. L. Comprehensive study on regional

human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique. Eur. J.

Pharm. Sci. 2013, 48 (1-2), 166-180.

http://dx.doi.org/10.1016/j.ejps.2013.01.015

SI24

121. Fenneteau, F.; Turgeon, J.; Couture, L.; Michaud, V.; Li, J.; Nekka, F. Assessing drug distribution in tissues

expressing P-glycoprotein through physiologically based pharmacokinetic modeling: model structure and parameters

determination. Theor. Biol. Med. Model. 2009, 6 (2), 1-13.

122. Mizuuchi, H.; Katsura, T.; Hashimoto, Y.; Inui, K.-i. Transepithelial Transport of Diphenhydramine Across

Monolayers of the Human Intestinal Epithelial Cell Line Caco-2. Pharm Res 2000, 17 (5), 539-545.

123. Willmann, S.; Schmitt, W.; Keldenich, J.; Lippert, J.; Dressman, J. B. A Physiological Model for the Estimation

of the Fraction Dose Absorbed in Humans. J Med Chem 2004, 47, 4022-4031.

124. Rinaki, E.; Valsami, G.; Macheras, P. Quantitative biopharmaceutics classification system: the central role of

dose/solubility ratio. Pharm. Res. 2003, 20 (12), 1917-1925.

125. Lima, J. L.; Haughey, D. B.; Leier, C. V. Disopyramide pharmacokinetics and bioavailability following

simultaneous administration of disopyramide and 14

C-disopyramide. J. Pharmacokinet. Biopharm. 1984, 12, 289-312.

126. Dressman, J. B.; Thelen, K.; Jantratid, E. Towards quantitative prediction of oral drug absorption. Clin

Pharmacokinet 2008, 47 (10), 655-667.

127. Yavuz, B.; Bilensoy, E.; Vural, I.; Sumnu, M. Alternative oral exemestane formulation: Improved dissolution and

permeation. Int. J. Pharm. 2010, 398, 137-145.

128. Okumu, A.; DiMaso, M.; Lobenberg, R. Computer simulations using GastroPlus to justify a biowaiver for

etoricoxib solid oral drug products. Eur J Pharm Biopharm 2009, 72 (1), 91-98.

129. Kubota, K.; Kurebayashi, H.; Miyachi, H.; Tobe, M.; Onishi, M.; Isobe, Y. Synthesis and structure–activity

relationships of phenothiazine carboxylic acids having pyrimidine-dione as novel histamine H1 antagonists. Bioorg. Med.

Chem. Lett. 2009, 19, 2766–2771.

130. Petri, N.; Tannergren, C.; Rungstad, D.; Lennernas, H. Transport characteristics of fexofenadine in the caco-2 cell

model. Pharm. Res. 2004, 21, 1398–1404.

131. Lemberger, L.; Bergstrom, R. F.; Wollen, R. L.; Farid, A.; Enas, G. G.; Aronoff, G. R. Fluoxetine: clinical

pharmacology and physiological disposition. J. Clin. Psychiatry 1985, 46, 14-19.

132. Zuo, Z.; Kwon, G.; Stevenson, B.; Diakur, J.; Wiebe, L. I. Flutamine-Hydroxypropyl-b-cyclodextrin Complex:

Formulation, Physical Characterization, and Absorption Studies using Caco-2 in vitro Model. J. Pharm. Pharm. Sci.

2000, 3 (2), 220-227.

133. Verwei, M.; van den Berg, H.; Havenaar, R.; Groten, J. P. Effect of folate-binding protein on intestinal transport

of folic acid and 5-methyltetrahydrofolate across Caco-2 cells. Eur. J. Nutr. 2005, 44, 242–249.

134. Geuns, J. M.; Augustijns, P.; Mols, R.; Buyse, J. G.; Driessen, B. Metabolism of stevioside in pigs and intestinal

absorption characteristics of stevioside, rebaudioside A and steviol. Food Chem. Toxicol. 2003, 41 (11), 1599-1607.

135. Turco, L.; Catone, T.; Caloni, F.; Consiglio, E. D.; Testai, E.; Stammati, A. Caco-2/TC7 cell line characterization

for intestinal absorption: How reliable is this in vitro model for the prediction of the oral dose fraction absorbed in

human? Toxicol In Vitro 2010, 25, 13–20.

136. Markowska, M.; Oberle, R.; Juzwin, S.; Hsu, C. P.; Gryszkiewicz, M.; Streeter, A. J. Optimizing Caco-2 cell

monolayers to increase throughput in drug intestinal absorption analysis. J Pharmacol Toxicol Methods 2001, 46 (1), 51-

55.

137. Cundy, K. C.; Branch, R.; Chernov-Rogan, T.; Dias, T.; Estrada, T.; Hold, K.; Koller, K.; Liu, X.; Mann, A.;

Panuwat, M.; Raillard, S. P.; Upadhyay, S.; Wu, Q. Q.; Xiang, J. N.; Yan, H.; Zerangue, N.; Zhou, C. X.; Barrett, R. W.;

Gallop, M. A. XP13512, A Novel Gabapentin Prodrug: 1. Design, Synthesis, Enzymatic Conversion to Gabapentin, and

Transport by Intestinal Solute Transporters. J Pharmacol Exp Ther 2004.

138. Stewart, B. H.; Chan, O. H.; Lu, R. H.; Reyner, E. L.; Schmid, H. L.; Hamilton, H. W.; Steinbaugh, B. A.; Taylor,

M. D. Comparison of intestinal permeabilities determined in multiple in vitro and in situ models: relationship to

absorption in humans. Pharm. Res. 1995, 12 (5), 693-699.

139. Gram, L. K.; Rist, G. M.; Lennernäs, H.; Steffansen, B. Impact of carriers in oral absorption: Permeation across

Caco-2 cells for the organic anions estrone-3-sulfate and glipizide. Eur. J. Pharm. Sci. 2009, 37, 378–386.

140. Adibi, S. A.; Gray, S. J.; Menden, E. The kinetics of amino acid absorption and alteration of plasma composition

of free amino acids after intestinal perfusion of amino acid mixtures. Am J Clin Nutr. 1967, 20 (1), 24-33.

141. Efthymiopoulos, C. Pharmacokinetics of grepafloxacin. J. Antimicrob. Chemother. 1997, 40 (Suppl. A), 35-43.

142. Sanghvi, T.; Ni, N.; Mayersohn, M.; Yalkowsky, S. H. Predicting passive intestinal absorption using a single

parameter. QSAR Comb Sci 2003, 22, 247-257.

143. Chiou, W. L.; Riegelman, S. Absorption characteristics of solid dispersed and micronized griseofulvin in man. J.

Pharm. Sci. 1971, 60 (9), 1376-1380.

144. Marino, A. M.; Yarde, M.; Patel, H.; Chong, S.; Balimane, P. V. Validation of the 96 well Caco-2 cell culture

model for high throughput permeability assessment of discovery compounds. Int. J. Pharm. 2005, 297 (1-2), 235-241.

145. Cruciani, G.; Crivori, P.; Carrupt, P. A.; Testa, B. Molecular fields in quantitative structure–permeation

relationships: the VolSurf approach. J. Mol. Struct. (THEOCHEM) 2000, 503 (1-2), 17-30.

SI25

146. Zhao, Y. H.; Abraham, M. H.; Le, J.; Hersey, A.; Luscombe, C. N.; Beck, G.; Sherborne, B.; Cooper, I.

Evaluation of rat intestinal absorption data and correlation with human intestinal absorption. Eur. J. Med. Chem. 2003,

38, 233-243.

147. De Souza, J.; Benet, L. Z.; Huang, Y.; Storpirtis, S. Comparison of Bidirectional Lamivudine and Zidovudine

Transport Using MDCK, MDCK–MDR1, and Caco-2 Cell Monolayers. J. Pharm. Sci. 2009, 98 (11), 4413-4419.

148. Humpel, M.; Nieuweboer, B.; Hasen, S. H.; Wendt, H. Radioimmunoassay of plasma lisuride in man following

intravenous and oral administration of lisuride hydrogen maleate; effect of prolactin level. Eur. J. Clin. Pharmacol. 1981,

20, 47-51.

149. Crowe, A.; Teoh, Y.-K. Limited P-glycoprotein mediated efflux for anti-epileptic drugs. J. Drug Target. 2006, 14

(5), 291-300.

150. Agarwal, S.; Boddu, S. H. S.; Jain, R.; Samanta, S.; Pal, D.; Mitra, A. K. Peptide Prodrugs: Improved Oral

Absorption of Lopinavir, a HIV Protease Inhibitor. Int. J. Pharm. 2008, 359 (1-2), 7–14.

151. Hou, T.; Xu, X. ADME evaluation in drug discovery. 1. Applications of genetic algorithms to the prediction of

blood-brain partitioning of a large set of drugs. J Mol Model (Online) 2002, 8 (12), 337-349.

152. Chikhale, P. J.; Borchardt, R. T. Metabolism of L-a-methyldopa in cultured human intestinal epithelial (Caco-2)

cell monolayers: Comparison with metabolism in vivo. Drug Metab. Dispos. 1994, 22, 592–600.

153. Oka, A.; Oda, M.; Saitoh, H.; Nakayama, A.; Takada, M.; Aungst, B. J. Secretory transport of

methylprednisolone possibly mediated by P-glycoprotein in Caco-2 cells. Biol Pharm Bull 2002, 25 (3), 393-396.

154. Ungell, A. L.; Artursson, P., An Overview of Caco-2 and Alternatives for Prediction of Intestinal Drug Transport

and Absorption. In Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability, Second

ed.; Han van de Waterbeemd; Testa, B., Eds. WILEY-VCH: Weinheim, 2008; 'Vol.' 40, pp 133-159.

155. Meylan, M. W.; Howard, P. H.; Boethling, R. S. Improved method for estimating water solubility from octanol

water partition coefficient. Environ. Toxicol. Chem. 1996, 15, 100-106.

156. Brown, L.; Heyneke, O.; Brown, D.; vanWyk, J. P. H.; Hamman, J. H. Impact of traditional medicinal plant

extracts on antiretroviral drug absorption. J. Ethnopharmacol. 2008, 119, 588–592.

157. Delchier, J. C.; Guerret, M.; Vidon, N.; Dubray, C.; Lavene, D. Influence of digestive secretions and food on

intestinal absorption of nicardipine. Eur. J. Clin. Pharmacol. 1988, 34, 165-171.

158. Adhami, Z.; Wise, R.; Weston, D.; Crump, B. The pharmacokinetics and tissue penetration of norfloxacin. J.

Antimicrob. Chemother. 1984, 13, 87-92.

159. Sugano, K.; Takata, N.; Machida, M.; Saitoh, K.; Terada, K. Prediction of passive intestinal absorption using bio-

mimetic artificial membrane permeation assay and the paracellular pathway model. Int J Pharm 2002, 241 (2), 241-251.

160. Chu, K. A.; Yalkowsky, S. H. An interesting relationship between drug absorption and melting point. Int. J.

Pharm. 2009, 373 (1-2), 24-40.

161. Kotecha, J.; Shah, S.; Rathod, I.; Subbaiah, G. Prediction of oral absorption in humans by experimental

immobilized artificial membrane chromatography indices and physicochemical descriptors. Int. J. Pharm. 2008, 360 (1-

2), 96-106.

162. Oulianova, N.; Cheng, D.; Huebert, N. D.; Chen, Y. Human oral drugs absorption is correlated to their in vitro

uptake by brush border membrane vesicles. Int. J. Pharm. 2007, 336 (1-2), 115-121.

163. Ma, L.; Yang, X. W. Absorption of papaverine, laudanosine and cepharanthine across human intestine by using

human Caco-2 cells monolayers model. Yao Xue Xue Bao. 2008, 43 (2), 202-207.

164. Kalantzi, L.; Reppas, C.; Dressman, J. B.; Amidon, G. L.; Junginger, H. E.; Midha, K. K.; Shah, V. P.;

Stavchansky, S. A.; Barends, D. M. Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms:

Acetaminophen (Paracetamol). J. Pharm. Sci. 2006, 95 (1), 4-14.

165. Kimura, Y.; Hosoda, Y.; Shima, M.; Adachi, S.; Matsuno, R. Physico-chemical Properties of Fatty Acids for

Assessing the Threshold Concentration to Enhance the Absorption of a Hydrophilic Substance. Biosci. Biotechnol.

Biochem. 1998, 62 (3), 443-447.

166. Fan, J.; Maeng, H.-J.; Du, Y.; Kwan, D.; Pang, K. S. Transport of 5,5-diphenylbarbituric acid and its precursors

and their effect on P-gp, MRP2 and CYP3A4 in Caco-2 and LS180 cells. Eur. J. Pharm. Sci. 2011, 42, 19-29.

167. Avdeef, A.; Tam, K. Y. How well can the Caco-2/Madin-Darby canine kidney models predict effective human

jejunal permeability? J Med Chem 2010, 53 (9), 3566-3584.

168. Löbenberg, R.; Amidon, G. L. Modern bioavailibility, bioequivalence and biopharmaceutics classification

system. New scientific approaches to intestinal regulatory standards. Eur. J. Pharm. Sci. 2000, 50, 3-12.

169. Motohashi, H.; Katsura, T.; Saito, H.; Inui, K. Effects of Tacrolimus and Cyclosporin A on Peptide Transporter

PEPT1 in Caco-2 Cells. Pharm. Res. 2001, 18 (5), 713-717.

170. Avdeef, A.; Tam, K. Y. How Well Can the Caco-2/Madin-Darby Canine Kidney Models Predict Effective

Human Jejunal Permeability? J. Med. Chem. 2010, 53, 3566-3584.

171. Serra, H.; Mendes, T.; Bronze, M. R.; Simplicio, A. L. Prediction of intestinal absorption and metabolism of

pharmacologically active flavones and flavanones. Bioorg Med Chem 2008, 16 (7), 4009-4018.

SI26

172. Othman, A. A.; Syed, S. A.; Newman, A. H.; Eddington, N. D. Transport, Metabolism, and in Vivo Population

Pharmacokinetics of the Chloro Benztropine Analogs, a Class of Compounds Extensively Evaluated in Animal Models

of Drug Abuse. J. Pharmacol. Exp. Ther. 2007, 320 (1), 344–353.

173. Ribadeneira, M. D.; Aungst, B. J.; Eyermann, C. J.; Huang, S. M. Effects of structural modifications on the

intestinal permeability of angiotensin II receptor antagonists and the correlation of in vitro, in situ, and in vivo

absorption. Pharm Res 1996, 13 (2), 227-233.

174. Siccardi, D.; Kandalaft, L. E.; Gumbleton, M.; McGuigan, C. Stereoselective and concentration-dependent

polarized epithelial permeability of a series of phosphoramidate triester prodrugs of d4T: an in vitro study in Caco-2 and

Madin-Darby canine kidney cell monolayers. J Pharmacol Exp Ther 2003, 307 (3), 1112-1119.

175. Trifilieff, A.; Wyss, D.; Walker, C.; Mazzoni, L.; Hersperger, R. Pharmacological Profile of a Novel

Phosphodiesterase 4 Inhibitor, 4-(8-Benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic Acid (NVP-ABE171), a

1,7-Naphthyridine Derivative, with Anti-Inflammatory Activities. J. Pharmacol. Exp. Ther. 2002, 301 (1), 241–248.

176. Van Voorhis, W. C.; Rivas, K. L.; Bendale, P.; Nallan, L.; Hornéy, C.; Barrett, L. K.; Bauer, K. D.; Smart, B. P.;

Ankala, S.; Hucke, O.; Verlinde, C. L. M. J.; Chakrabarti, D.; Strickland, C.; Yokoyama, K.; Buckner, F. S.; Hamilton,

A. D.; Williams, D. K.; Lombardo, L. J.; Floyd, D.; Gelb, M. H. Efficacy, Pharmacokinetics, and Metabolism of

Tetrahydroquinoline Inhibitors of Plasmodium falciparum Protein Farnesyltransferase. Antimicrob. Agents Chemother.

2007, 51 (10), 3659–3671.

177. Zhang, L.; Yu, H.; Li, W. M.; Cheung, M. C.; Pang, Y. P.; Gu, Z. M.; Chan, K.; Wang, Y. T.; Zuo, Z.; Han, Y. F.

Preclinical characterization of intestinal absorption and metabolism of promising anti-Alzheimer’s dimer bis(7)-tacrine.

Int. J. Pharm. 2008, 357, 85–94.

178. Zielinska-Dawidziak, M.; Grajek, K.; Olejnik, A.; Czaczyk, K.; Grajek, W. Transport of High Concentration of

Thiamin, Riboflavin and Pyridoxine across Intestinal Epithelial Cells Caco-2. J. Nutr. Sci. Vitaminol. 2008, 54, 423-429.

179. Ahmad, R. A.; Rogers, H. J. Pharmacokinetics and Protein Binding Interactions of Dapsone and Pyrimethamine.

Br. J. Clin. Pharmacol. 1980, 10, 519-524.

180. Fuder, H.; Herzog, R.; W., V.; Wetzelsberger, N.; Lucker, P. W. Study on the absolute bioavailability of quinine

and theophylline from tablets after single dose oral administration as compared to intravenous infusion in healthy male

non-smoking volunteers. Methods Find Exp. Clin. Pharmacol. 1994, 16 (9), 651-660.

181. Strauch, S.; Dressman, J. B.; Shah, V. P.; Kopp, S.; Polli, J. E.; Barends, D. M. Biowaiver Monographs for

Immediate-Release Solid Oral Dosage Forms: Quinine Sulfate. J. Pharm. Sci. 2011, 101 (2), 499-508.

182. Jeong, E. J.; Lin, H.; Hu, M. Disposition mechanisms of raloxifene in the human intestinal Caco-2 model. J

Pharmacol Exp Ther 2004, 310 (1), 376-385.

183. Crowe, A.; Lemaire, M. In vitro and in situ absorption of SDZ-RAD using a human intestinal cell line (Caco-2)

and a single pass perfusion model in rats: comparison with rapamycin. Pharm Res 1998, 15 (11), 1666-1672.

184. Mukaizawa, F.; Taniguchi, K.; Miyake, M.; Ogawara, K.; Odomi, M.; Higaki, K.; Kimura, T. Novel oral

absorption system containing polyamines and bile salts enhances drug transport via both transcellular and paracellular

pathways across Caco-2 cell monolayers. Int. J. Pharm. 2009, 367, 103–108.

185. Klopman, G.; Stefan, L. R.; Saiakhov, R. D. ADME evaluation. 2. A computer model for the prediction of

intestinal absorption in humans. Eur. J. Pharm. Sci. 2002, 17 (4-5), 253-263.

186. Hendriksen, B. A.; Felix, M. V.; Bolger, M. B. The composite solubility versus pH profile and its role in

intestinal absorption prediction. AAPS PharmSci 2003, 5 (1), E4.

187. Ranaldi, G.; Seneci, P.; Guba, W.; Islam, K.; Sambuy, Y. Transport of the Antibacterial Agent Oxazolidin-2-One

and Derivatives across Intestinal (Caco-2) and Renal (MDCK) Epithelial Cell Lines. Antimicrob. Agents Chemother.

1996, 40 (3), 652–658.

188. Zhu, H.-J.; Wang, J.-S.; Markowitz, J. S.; Donovan, J. L.; Gibson, B. B.; DeVane, C. L. Risperidone and

Paliperidone Inhibit P-Glycoprotein Activity In Vitro. Neuropsychopharmacology 2007, 32, 757–764.

189. Pachot, J. I.; Botham, R. P.; Haegele, K. D.; Hwang, K. Experimental estimation of the role of P-Glycoprotein in

the pharmacokinetic behaviour of telithromycin, a novel ketolide, in comparison with roxithromycin and other

macrolides using the Caco-2 cell model. J. Pharm. Pharm. Sci. 2003, 6 (1), 1-12.

190. Mihaly, G. W.; Ward, S. A.; Edwards, G.; Orme, M. L.; Breckenridge, A. M. Pharmacokinetics of primaquine in

man: Identification of the carboxylic acid derivative as a major plasma metabolite. Br. J. Clin. Pharmacol. 1984, 17 (4),

441-446.

191. Nair, A.; Abrahamsson, B.; Barends, D. M.; Groot, D. W.; Kopp, S.; Polli, J. E.; Shah, V. P.; Dressman, J. B.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Primaquine Phosphate. J. Pharm. Sci. 2012,

101 (3), 936-945.

192. Valenzuela, B.; Martín-Villodre, A.; Nácher, A. In Estudio de la permeabilidad del Salbutamol en células Caco-

2: Con TC7, VI Congreso SEFIG & 3ª Jornada TF. Biofarmacia y Farmacocinética, pp 381-383.

SI27

193. You, H. S.; Zhang, H. F.; Dong, Y. L.; Chen, S. Y.; Wang, M. Y.; Dong, W. H.; Xing, J. F. Absorption and

transportation characteristics of scutellarin and scutellarein across Caco-2 monolayer model. Zhong Xi Yi Jie Hue Xue

Bao. 2010, 8 (9), 863-869.

194. Celewicz, L.; Józwiak, A.; Ruszkowski, P.; Laskowska, H.; Olejnik, A.; Czarnecka, A.; Hoffmann, M.; Hładon,

B. Synthesis and anticancer activity of 5'-chloromethylphosphonates of 3'-azido-3'-deoxythymidine (AZT). Bioorg. Med.

Chem. 2011, 19, 6375–6382.

195. Karim, A.; Zagarella, J.; Hutsell, T. C.; Chao, A.; J., B. B. Spironolactone. II. Bioavailability. Clin. Pharmacol.

Ther. 1976, 19, 170-176.

196. Takano, M.; Hasegawa, R.; Fukuda, T.; Yumoto, R.; Nagai, J.; Murakami, T. Interaction with P-glycoprotein and

transport of erythromycin, midazolam and ketoconazole in Caco-2 cells. Eur J Pharmacol 1998, 358 (3), 289-294.

197. Liang, E.; Proudfoot, J.; Yazdanian, M. Mechanisms of transport and structure-permeability relationship of

sulfasalazine and its analogs in Caco-2 cell monolayers. Pharm. Res. 2000, 17 (10), 1168-1174.

198. Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based

contributions and its application to the prediction of drug transport properties. J. Med. Chem. 2000, 43 (20), 3714-3717.

199. Kansy, M.; Senner, F.; Gubernator, K. Physicochemical high throughput screening: parallel artificial membrane

permeation assay in the description of passive absorption processes. J. Med. Chem. 1998, 41 (7), 1007-1010.

200. Rozehnal, V.; Nakai, D.; Hoepner, U.; Fischer, T.; Kamiyama, E.; Takahashi, M.; Yasuda, S.; Mueller, J. Human

small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of

drugs. Eur. J. Pharm. Sci. 2012, 46 (5), 367-373.

201. Tavelin, S.; Taipalensuu, J.; Hallbook, F.; Vellonen, K. S.; Moore, V.; Artursson, P. An improved cell culture

model based on 2/4/A1 cell monolayers for studies of intestinal drug transport: characterization of transport routes.

Pharm Res 2003, 20 (3), 373-381.

202. Zhou, S.; Li, Y.; Kestell, P.; Paxton, J. W. D etermination of thalidomide in transport buffer for Caco-2 cell

monolayers by high-performance liquid chromatography with ultraviolet detection. J Chromatogr B 2003, 785, 165–173.

203. Thiel-Demby, V. E.; Humphreys, J. E.; St John Williams, L. A.; Ellens, H. M.; Shah, N.; Ayrton, A. D.; Polli, J.

W. Biopharmaceutics classification system: validation and learnings of an in vitro permeability assay. Mol.

Pharmaceutics 2009, 6 (1), 11-18.

204. Davis, S. S.; Khosla, R.; Wilson, C. G.; Washington, N. Gastrointestinal transit of a controlled-release pellet

formulation of tiaprofenic acid and the effect of food. Int. J. Pharm. 1987, 35, 253-258.

205. Nishimura, N.; Naora, K.; Uemura, T.; Hirano, H.; Iwamoto, K. Transepithelial permeation of tolbutamide across

the human intestinal cell line, Caco-2. Drug Metab Pharmacokinet 2004, 19 (1), 48-54.

206. Gunturi, S. B.; Narayanan, R. In Silico ADME Modeling 3: Computational Models to Predict Human Intestinal

Absorption Using Sphere Exclusion and kNN QSAR Methods. QSAR Comb. Sci. 2007, 26 (5), 653 – 668.

207. Kanaan, M.; Daali, Y.; Dayer, P.; Desmeules, J. Uptake/Efflux Transport of Tramadol Enentiomers and O-

Desmethyl-Tramadol: Focus on P-Glycoprotein. Basic Clin Pharmacol Toxicol 2009, 105, 199-206.

208. Landowski, C. P.; Song, X.; Lorenzi, P. L.; Hilfinger, J. M.; Amidon, G. L. Floxuridine amino acid ester

prodrugs: enhancing Caco-2 permeability and resistance to glycosidic bond metabolism. Pharm Res 2005, 22 (9), 1510-

1518.

209. Zhao, Y. H.; Abraham, M. H.; Hersey, A.; Luscombe, C. N. Quantitative relationship between rat intestinal

absorption and Abraham descriptors. Eur. J. Med. Chem. 2003, 38 (11-12), 939-947.

210. Engman, H.; Tannergren, C.; Artursson, P.; Lennernas, H. Enantioselective transport and CYP3A4-mediated

metabolism of R/S-verapamil in Caco-2 cell monolayers. Eur J Pharm Sci 2003, 19 (1), 57-65.

211. Chiou, W. L.; Jeong, H. Y.; Chung, S. M.; Wu, T. C. Evaluation of using dog as an animal model to study the

fraction of oral dose absorbed of 43 drugs in humans. Pharm. Res. 2000, 17 (2), 135-140.

212. Eriksson, T.; Bjorkman, S.; Hoglund, P. Clinical pharmacology of thalidomide. Eur. J. Clin. Pharmacol. 2001, 57

(5), 365-376.

213. Ma, L.; Yang, X. W. Studies on predict of absorption of corynanthine, yohimbine, ajmalicine and ajmaline across

human intestinal epithelial by using human Caco-2 cells monolayers. Zhongguo Zhong Yao Za Zhi. 2008, 33 (20), 2373-

2377.

214. Galijatovic, A.; Walle, U. K.; Walle, T. Induction of UDP-Glucuronosyl- Transferase by the Flavonoids Chrysin

and Quercetin in Caco-2 Cells. Pharm Res 2000, 17 (1), 21-26.

215. Li, C.; Uss, A. S.; Cheng, K. C., Use of Permeability from Cultured Cell Lines and PAMPA System and

Absorption from Experimental Animals for the Prediction of Absorption in Humans. In Methods in Bioengineering:

Alternative Technologies to Animal Testing, Maguire, T.; Novik, E., Eds. Artech House: Boston, USA, 2010; pp 19-40.

216. The International Pharmacopoeia. 4th ed.; World Health Organization: WHO Press, 20 Avenue Appia, 1211

Geneva 27, Switterland, 2006; Vol. 1 & 2, p 1520.

217. The Merck Index. 14th ed.; Merck Research Laboratories: Whitehouse Station, N.J., USA.

SI28

218. Yalkowsky, S. H.; Yan., H.; Jain, P., Handbook of Aqueous Solubility Data. Second ed.; Taylor & Francis Group

LLC: 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742, USA, 2010; p 1608.

219. Fell, J. T.; Calvert, R. T.; Riley-Bentham, P. Bioavailability of griseofulvin from a novel capsule formulation. J.

Pharm. Pharmacol. 1978, 30, 479-482.

220. Crowe, A.; Bruelisauer, A.; Duerr, L.; Guntz, P.; M, L. Absorption and Intestinal Metabolism of SDZ-RAD and

Rapamycin in Rats. Drug Metab. Dispos. 1999, 27 (5), 627-632

221. Satoskar, R. S.; Bhandark, S. D., Pharmacology and Pharmacotherapeutics. 18th ed.; Popular Prakashan Pvt Ltd.:

Mumbai India, 2003; p 1130.

222. Rongen, G. A.; Lenders, J. W. M.; Smits, P.; Thien, T. Clinical pharmacokinetics and efficacy of renin inhibitors.

Clin. Pharmacokinet. 1995, 29 (1), 6-14.

223. Becker, C.; Dressman, J. B.; Junginger, H. E.; Kopp, S.; Midha, K. K.; Shah, V. P.; Stavchansky, S.; Barends, D.

M. Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Rifampicin. J. Pharm. Sci. 2009, 98 (7),

2252-2267.

224. Hutching, M. J.; Paull, J. D.; Wilson, E. E.; Morgan, D. J. Pharmacokinetics and metabolism of Salbutamol in

premature labour. Br. J. Clin. Pharmacol. 1987, 24 (1), 69-75.

225. Pacifici, G. M.; Giulianetti, B.; Quilici, M. C.; Spisni, R.; Nervi, M.; Giuliani, L.; Gomeni, R. Salbutamol

sulphation in the human liver and duodenal mucosa: interindividual variability. Xenobiotica 1997, 27 (3), 279-286.

226. Price, A. H.; Clissold, S. P. Salbutamol in the 1980s: A Reappraisal of its Clinical Efficacy. Drugs 1989, 38 (1),

77-122.

227. Taburet, A. M.; Schmit, B. Pharmacokinetic optimisation of Asthma Treatment. Clin. Pharmacokinet. 1994, 26

(5), 396-418.

228. Sakuma, S.; Tachiki, H.; Uchiyama, H.; Fukui, Y.; Takeuchi, N.; Kumamoto, K.; Satoh, T.; Yamamoto, Y.; Ishii,

E.; Sakai, Y.; Takeuchi, S.; Sugita, M.; Shinji, Y. A Perspective for Biowaivers of Human Bioequivalence Studies on the

Basis of the Combination of the Ratio of AUC to the Dose and the Biopharmaceutics Classification System. Mol.

Pharmaceutics 2011, 8, 1113-1119.

229. Dresser, G. K.; Bailey, D. G. A basic conceptual and practical overview of interactions with highly prescribed

drugs. Can. J. Clin. Pharmacol. 2002, 9 (4), 191-198.

230. Neuvonen, P. J.; Kantola, T.; Kivisto, K. T. Simvastatin but not Pravastatin is very susceptible to interaction with

the CYP3A4 inhibitor itraconazole. Clin. Pharmacol. Ther. 1998, 63, 332-341.

231. Silva, A. L. L.; Cristofoletti, R.; Storpirtis, S.; Sousa, V. D.; Hans, E. J.; Shah, V. P.; Stavchansky, S.; Dressman,

J. B.; Barends, D. M. Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Stavudine. J. Pharm.

Sci. 2011, 101 (1), 10-16.

232. Khandelwal, A.; Bahadduri, P. M.; Chang, C.; Polli, J. E.; Swaan, P. W.; Ekins, S. Computational models to

assign biopharmaceutics drug disposition classification from molecular structure. Pharm. Res. 2007, 24 (12), 2249-2262.

233. Gres, M. C.; Julian, B.; Bourrie, M.; Meunier, V.; Roques, C.; Berger, M.; Boulenc, X.; Berger, Y.; Fabre, G.

Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial

intestinal cell line: comparison with the parental Caco-2 cell line. Pharm Res 1998, 15 (5), 726-733.

234. HG., C.; Lee, B. J.; Han, J. H.; Lee, M. K.; Park, K. M.; Yong, C. S.; Rhee, J. D.; Kim, Y. B.; Kim, C. K.

Terfenadine-beta-Cyclodextrin inclusion complex with antihistaminic activity enhancement. Drug Dev. Ind. Pharm.

2001, 27 (8), 857-862.

235. Okerholm, R. A.; Weiner, D. L.; Hook, R. H.; Walker, B. J.; Leeson, G. A.; Biedenbach, S. A.; Cawein, M. J.;

Dusebout, T. D.; Wright, G. J.; Myers, M.; Schindler, V.; Cook, C. E. Bioavailability of terfenadine in man. Biopharm.

Drug Dispos. 1981, 2 (2), 185-190.

236. Poirier, A.; Cascais, A.-C.; Funk, C.; Lavé, T. Prediction of pharmacokinetic profile of valsartan in human based

on in vitro uptake transport data. J. Pharmacokinet. Pharmacodyn. 2009, 36, 585-611.

237. Absorption. In Pharmacokinetics and Metabolism in Drug Design, Smith, D. A.; Van de Waterbeemd, H.;

Walker, D. K., Eds. Wiley-VCH Verlag GmbH: Weinheim, Germany, 2001; pp 35-46.

238. Balon, K.; Riebesehl, B. U.; Muller, B. W. Drug liposome partitioning as a tool for the prediction of human

passive intestinal absorption. Pharm. Res. 1999, 16 (6), 882-888.

239. Tetko, I. V.; Bruneau, P. Application of ALOGPS to Predict 1-Octanol/Water Distribution Coefficients, logP, and

logD, of AstraZeneca In-House Database. J. Pharm. Sci. 2004, 93 (12), 3103-3110.

240. Moriguchi, I.; Hirono, S.; Liu, Q.; Nakagome, I.; Matsushita, Y. Simple method of calculating octanol/water

partition coefficient. Chem. Pharm. Bull. 1992, 40, 127–130.

241. Moriguchi, I.; Hirono, S.; Nakagome, I.; Hirano, H. Comparison of reliability of logP values for drugs calculated

by several methods. Chem. Pharm. Bull. 1994, 42, 976–978.

242. DRAGON for Windows (Software for Molecular Descriptor Calculator). 6.0; Talete srl, Milano Chemometrics

and QSAR Research Group: http://www.talete.mi.it/products/dragon_description.htm.

http://www.talete.mi.it/products/dragon_description.htm

SI29

243. Todeschini, R.; Consonni, V., Molecular Descriptors for Chemoinformatics. Wiley VCH Verlag GmbH & Co.:

Weinheim, Germany, 2009; Vol. I & II.

244. Tetko, I. V. Computing chemistry on the web. Drug Discov. Today 2005, 10 (22), 1497-1500.

245. VolSurf+, version 1.0.4; available from Molecular Discovery Ltd., London, U.K. (http://www.moldiscovery.com).

http://www.moldiscovery.com)/

SI1

SUPPORTING INFORMATION (Nº2)

Provisional Classification and in silico Study of Biopharmaceutical System based on

Caco-2 cell Permeability and Dose number

Hai Pham-The†, Teresa M. Garrigues

§, Marival Bermejo

‡, Isabel González Álvarez

‡, Maikel Cruz-

Monteagudo∇,∥,⊥, and Miguel Ángel Cabrera-Pérez*

,†,§,‡

†Molecular Simulation & Drug Design Group. Centre of Chemical Bioactive. Central University of Las Villas.

Santa Clara 54830, Villa Clara, Cuba; §Department of Pharmacy and Pharmaceutical Technology, University of

Valencia, Burjassot 46100, Valencia, Spain; ‡Department of Engineering, Area of Pharmacy and Pharmaceutical

Technology, Miguel Hernández University, 03550 Sant Joan d'Alacant, Alicante, Spain; ∇CIQ, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal; ∥REQUIMTE, Department f Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal; ⊥Applied Chemistry Research Center (CEQA), Faculty of Chemistry and Pharmacy, Central University of Las Villas. Santa Clara, 54830, Cuba

*To whom correspondence should be addressed: Molecular Simulation & Drug Design Group. Centre of Chemical Bioactive. Central University of Las Villas. Santa Clara 54830, Villa Clara, Cuba. E-mail: [email protected]; [email protected]; [email protected] Phone/fax: 53-42-281192 / 53-42-281130

SI2

Figure SI1. Correlations between Dose number and: (A1) minimum aqueous solubility between pH ranges of

1.2-6.8 at 37°C (Smin), (A2) maximum aqueous solubility between pH ranges of 1.2-6.8 at 37°C (Smax), (B1)

drug’s highest dose strength (Dmax), and (B2) drug’s lowest dose strength (Dmin). Arrows in (A2) and (B2)

indicate the translocations of solubility classification (from low to high class) when Smax and Dmin were used.

STATISTICAL MODELS

The selection of models for consensus was carried out by mean of general comparison of calculated

performances. Predictions on the test set are the main criterion for model selection. Additionally, the principle of

maximal parsimony (Occam’s razor) was also taken into account. Therefore, we selected the model with highest

statistical signification having as few parameters (ak) as possible.

Table SI3. Confusion matrix1

Predicted as positive (+) Predicted as negative (-)

Actually positive (+) True positives (TP) False negatives (FN)

Actually negative (-) False positive (FP) True negatives (TN)

SI3

Solubility modeling

Table SI4. Performance comparison of the three obtained LDA models for PBC solubility classification

Equation Descriptor

family

MCC Accuracy Specificity Sensitivity Precision AUC (Ts)b

% (Tr/Ts)a

LDA (S1) 0-2D Dragon

plus Volsurf+ 0.66/0.54 83.3/76.9 82.2/79.3 84.0/75.0 86.9/81.8 0.88±0.04

LDA (S2) Volsurf+ 0.59/0.57 79.7/78.4 80.4/82.8 79.3/75.0 85.0/84.4 0.86±0.05

LDA (S3) 0-2D Dragon 0.57/0.55 78.5/77.8 79.1/77.8 78.2/77.8 83.3/82.4 0.87±0.05

Mathematical equations

CLASSDo(+/-) = –1.59 – 0.54×PˍVSAˍvˍ3 + 0.80×nArC=N + 0.65×C-005 – 0.84×CATS2Dˍ04ˍAL

+ 0.79×DLSˍ04 + 4.51×ID3 + 0.28×A – 0.41×LgD5

(S1)

N = 257 λ = 0.60 D2 = 2.74 F = 25.61 p < 0.0001

CLASSDo (+/-) = 1.03 + 0.01×S + 0.01×W5 + 0.25×WO5 – 0.03×HL2 + 0.01×DLSˍ04

– 0.04×PSA + 2.08×SOLY+ 1.20×L3LgS

(S2)

N = 257 λ = 0.67 D2 = 2.00 F = 18.86 p < 0.0001

CLASSDo (+/-) = 0.22 – 0.78×Me + 0.49×nR10 – 1.09×nCt + 0.77×nArC=N + 0.66×N-067

– 0.85×NssNH + 1.23×BLTD48 + 0.75×DLS_04 – 0.58×CMC-50

(S3)

N = 257 λ = 0.64 D2 = 2.30 F = 15.61 p < 0.0001

aMeasured performances of training/test set;

bArea under the ROC curve determined on test set by non-parametric

assumptions in 95% asymptotic confidence interval.

Table SI5. Performance comparison of the three obtained QDA models for PBC solubility classification

Equation Descriptor

family

MCC Accuracy Specificity Sensitivity Precision AUC (Ts)

% (Tr/Ts)

QDA (S1) 0-2D Dragon

plus Volsurf+ 0.63/0.60 82.1/80.0 78.2/79.3 85.0/80.6 83.9/82.9 0.86±0.05

QDA (S2) 0-2D Dragon 0.63/0.75 81.7/87.7 82.2/82.8 81.3/91.7 86.5/86.8 0.97±0.04

QDA (S3) Volsurf+ 0.60/0.60 80.5/80.0 76.4/82.8 83.7/77.8 82.6/84.8 0.89±0.04


CLASSDo (+/-) = – 0.93 – 0.60×LgD5 + 0.81×DLS_04 + 0.87×P_VSA_v_3×nArC=N – 0.21×P_VSA_v_3×A

– 0.79×CATS2D_04_AL + 0.01×C-005×D2 – 0.06×LgD52

+ 0.18×CATS2D_04_AL×LgD5 + 0.004×D2×A

(S1)

N = 257 λ = 0.58 D2 = 3.24 p < 0.0001

CLASSDo (+/-) = –0.36 – 0.90×Me – 1.40×nCt – 0.79×NssNH + 1.22×BLTD48 + 0.87×DLSˍ04

– 0.82×CMC-50 – 1.86×nArC=N×N-067 + 0.41×N-067×NssNH

– 0.73×Me×CMC-50 + 0.51×nR102

(S2)

N = 257 λ = 0.59 D2 = 2.88 p < 0.0001

CLASSDo (+/-) = –0.19 + 2.75×SOLY + 7.59×L3LgS – 0.00×MW×PSA + 0.02×S – 0.04×PSA

– 0.09×WO5×SOLY + 0.01×MW – 1.82×SOLY×L3LgS – 0.03×S×L3LgS + 0.02×PSA×L3LgS

(S3)

N = 257 λ = 0.63 D2 = 2.49 p < 0.0001

SI4

Table SI6. Performance comparison of the three obtained BLR models for PBC solubility classification

Equation Descriptor

family

MCC Accuracy Specificity Sensitivity Precision AUC (Ts)b

% (Tr/Ts)a

BLR (S1) 0-2D Dragon

plus Volsurf+ 0.61/0.63 80.9/81.5 76.4/82.8 84.4/80.6 82.7/85.3 0.88±0.04

BLR (S2) Volsurf+ 0.55/0.64 78.2/81.4 74.5/86.2 81.0/77.8 81.0/87.5 0.87±0.04

BLR (S3) 0-2D Dragon 0.60/0.69 80.5/84.6 75.5/82.1 84.1/86.5 83.0/86.5 0.96±0.03


Ln (P+/P-) = –0.31 – 0.52×CATS2D_09_DA + 1.52×DLS_05 + 0.33×A – 0.12×PSA

– 0.83×LgD5 + 2.59×nArC=N

(S1)

Ln (P+/P-) = 0.50 + 0.02×WO2 + 7.92×ID3 – 0.02×PSA – 0.69×LgD5 + 0.74×CACO2 (S2)

Ln (P+/P-) = 2.63 – 0.59×nCp + 4.44×nArC=N + 0.20×H-052 + 1.82×N-067 – 1.32×NssNH

+ 1.09×BLTD48 + 4.58×LDSˍ04 – 1.38×CMC-50 – 0.38×nO

(S3)




Comparisons of the ROC curve pathways can be observed in the Figure SI1.

Figure SI2: The Receiver Operating Characteristic (ROC) curves for solubility models obtained by three statistical

techniques.

SI5

Permeability modeling

Table SI7. Performance comparison of the three obtained LDA models for PBC permeability classification

Equation Descriptor

family


b

% (Tr/Ts)a

LDA (P1) 0-2D Dragon

plus Volsurf+

0.63/0.69 81.6/84.9 81.9/85.7 81.4/84.2 82.0/88.9 0.93±0.03

LDA (P2) 0-2D Dragon 0.63/0.63 81.4/81.8 81.4/82.1 81.9/81.6 81.3/86.1 0.91±0.03

LDA (P3) Volsurf+ 0.66/0.58 83.2/79.1 81.4/79.3 85.0/78.9 81.8/83.3 0.90±0.04


CLASSPapp(+/-) = –5.91 + 0.01×PˍVSAˍsˍ6 – 1.62×nRNR2 – 0.74×C-016 + 2.64×CATS2Dˍ08ˍAP

+ 4.23×LLSˍ01 + 0.01×WN2 + 3.79×CACO2

(P1)

N = 256 λ = 0.57 D2 = 2.81 F = 22.24 p < 0.0001

CLASSPapp(+/-) = –25.32 + 0.21×%C + 70.97×ChiA_B(v) + 8.73×MATS1e – 5.64×GATS2m

– 1.37×nRCOOH – 1.11×nRNR2 – 0.49×C-016 + 4.82×LLS_01

(P2)

N = 256 λ = 0.58 D2 = 2.66 F = 22.49 p < 0.0001

CLASSPapp(+/-) = 7.83 – 6.34×G + 0.03×W5 – 0.24×POL + 0.11×PSA – 34.27×PSAR

+ 0.04×PB + 4.70×CACO2 – 0.89×L3LgS

(P3)

N = 256 λ = 0.58 D2 = 2.86 F = 22.17 p < 0.0001




Table SI8. Performance comparison of the three obtained QDA models for PBC permeability classification

Equation Descriptor

family


% (Tr/Ts)

QDA (P1) 0-2D Dragon

plus Volsurf+

0.66/0.69 83.2/84.9 82.9/85.7 83.5/84.2 82.8/88.9 0.91±0.04

QDA (P2) 0-2D Dragon 0.65/0.76 82.4/87.9 81.1/89.3 83.7/86.8 81.8/91.7 0.94±0.03

QDA (P3) Volsurf+ 0.63/0.66 81.6/83.3 80.6/82.1 82.7/84.2 80.8/86.5 0.92±0.03


CLASSPapp(+/-) = –1.36 + 3.39×CACO2 – 5.04×nN(CO)2×CATS2D_08_AP – 0.97×nRNR2

– 0.24×LLS_01×DD4 + 1.11×P_VSA_s_6

+ 3.23×CATS2D_08_AP×B04[O-Cl]+ 0.69×LLS_01 + 0.36×CACO22

(P1)

N = 256 λ = 0.57 D2 = 3.06 p < 0.0001

CLASSPapp (+/-) = 0.32 – 1.02×GATS2m + 0.95×GATS2s – 0.55×nRNR2 – 0.52×B03[O-O]

– 1.95×SAdon + 0.82×LLS -01 + 3.46×nC=N-N<×B04[O-Cl]

+ 0.37×nRNR2×SAdon + 0.32×CATS2Dˍ03ˍDD×SAdon – 0.46×B08[C-O]2

(P2)

N = 256 λ = 0.55 D2 = 3.18 p < 0.0001

CLASSPapp(+/-) = –2.36 + 6.25×CACO2 – 0.03×POL×CACO2 – 0.0008×POL2

– 0.016×PB×L3LgS + 0.07×W5×PSAR + 0.0002×PSA×PB

(P3)

N = 256 λ = 0.59 D2 = 2.58 p < 0.0001

SI6

Table SI9. Performance comparison of the three obtained BLR models for PBC permeability classification

Equation Descriptor

family


% (Tr/Ts)

BLR (P1) Volsurf+ 0.63/0.66 81.6/83.3 80.6/78.6 82.7/86.8 80.8/84.6 0.90±0.04

BLR (P2) 0-2D Dragon 0.61/0.60 80.5/80.3 82.2/82.1 78.7/78.9 81.3/85.7 0.89±0.04

BLR (P3) 0-2D Dragon

plus Volsurf+ 0.64/0.73 82.0/86.4 79.5/89.3 84.5/84.2 80.7/91.4 0.92±0.03


Ln (P+/P-) = –15.61 + 0.02×WN2 + 0.06×PSA + 6.74×CACO2 + 0.06×MetStab

– 0.01×MW + 0.06×PB

(P1)

Ln (P+/P-) = 3.76 + 9.48×MATS1e + 1.75×GATS6e – 1.49×CATS2D_06_DD + 3.22×CATS2D_08_AP

+ 2.26×B07[N-F] – 6.64×GATS2m + 3.02×GATS2s – 0.92×Eig02_AEA(dm) + 7.49×Chi_Dz(p)

(P2)

Ln (P+/P-) = 5.49 – 2.05×nRNR2 + 3.74×CATS2Dˍ07ˍDP + 1.88×CACO2 – 5.04×GATS2m

– 22.48×nFuranes – 0.02×SAdon – 1.05×nRCOOH

(P3)

Comparisons of the ROC curve pathways can be observed in the Figure SI2.

Figure SI3: The Receiver Operating Characteristic (ROC) curves for Permeability models obtained by three statistical

techniques.

SI7

Table SI10. Descriptions of Dragon and Volsurf+ descriptors selected to build models shown in Table 2 and 3

Descriptor Description Impact

to class*

Solubility (Do)

Me Mean atomic Sanderson electronegativity (scaled on Carbon atom) ↓

nO Number of Oxygen atoms ↓

nR10 Number of 10-membered rings –

P_VSA_v_3 P_VSA-like on van der Waals volume, bin 3 ↓

nCp Number of terminal primary C(sp3) ↓

nCt Number of total tertiary C(sp3) ↓

nArC=N Number of imines (aromatic) ↑

C-005 CH3-X (X: any electronegative atom, e.g. O, N, S, P, Se or halogens) ↑

H-052 H attached to C0(sp3) with 1X attached to next C ↑

N-067 Al2-NH (Al: aliphatic groups) ↑

NssNH Number of atom of type ssNH (–NH2+–) ↓

CATS2D_04_AL CATS2D acceptor-lipophilic at lag 04 ↓

BLTD48 Verhaar Daphnia base-line toxicity from Mlog P (mmol/L) ↑

DLS_04 Modified drug-like score from Chen et al.2 (7 rules) ↑

CMC-50 Ghose-Viswanadhan-Wendoloski CMC drug-like index at 50%.3 ↓

ID3

Hydrophobic IntEgy (Interaction Energy) moment (distance between the centre of

mass of molecular and the centre of hydrophobic interactions around it) at enegy level

of -0.6 kcal/mol

↑

A Amphiphilic moment (measure of the distribution of the polar and non-polar groups in

the molecule) ↑

LgD5 Calculated logarithm of the distribution coefficient between 1-octanol and water (at

pH 5) ↓

Caco-2 Permeability

GATS2m Geary autocorrelation of lag 2 weighted by atomic masses ↓

GATS2s Geary autocorrelation of lag 2 weighted by I-state (ionization state) ↑

P_VSA_s_6 P_VSA-like on I-state, bin 6 ↑

nRCOOH Number of carboxylic acids (aliphatic) ↓

nRNR2 Number of tertiary amines (aliphatic) ↓

nC=N-N< Number of hydrazones ↑ (In

comb.)

nFuranes Number of Furanes ↓↓

C-016 =CHR ↓

CATS2D_03_DD Topological distance between potential pharmacophore point pairs encoded by

hydrogen bond donor-donor at lag 03

↑ (In

comb.)

CATS2D_07_DP Topological distance between potential pharmacophore point pairs encoded by

hydrogen bond donor-positively charged or ionizable atoms at lag 07 ↑

CATS2D_08_AP Topological distance between potential pharmacophore point pairs encoded by

hydrogen bond acceptor-positively charged or ionizable atoms at lag 08 ↑

B03[O-O] Presence/absence of O-O at topological distance 3 ↓

B04[O-Cl] Presence/absence of O-Cl at topological distance 4 ↑ (In

comb.)

B08[C-O] Presence/absence of C-O at topological distance 8 –

SAdon Surface area of donor atoms from P_VSA-like descriptors ↓

LLS_01 Modified lead-like score from Congreve et al.4 (6 rules) ↑

WN2 Hydrogen bond acceptor volume (using amide/nitrogen groups for GRID field

calculation at interaction energy level of -2 kcal/mol) ↑

CACO2 Caco-2 cell permeability predictions by Zamora et al.

5 (referred to as Absorption-

Distribution-Metabolism-Excretion, ADME, Volsurf descriptor) ↑

*Impact: ↑ positive, ↓ negative, – undefined, (In comb.) effect detected in variable combinations (e.g. ViVj)

SI8

Figure SI4. William’s plots based on solubility and permeability discriminant models for training, external set of 57 drugs

with BCS classified by WHO,6 and 675 drugs with BDDCS classification.

7 Warning leverages h* were determined as:

0.093 for LDA(S1), 0.117 for QDA(S2), 0.105 for BLR(S3), 0.082 for LDA(P2), 0.117 for QDA(P2) and 0.094 for

BLR(P3).

Figure SI5. William’s plots based on solubility and permeability models for training and large medicinal-chemistry

database predicted by Broccatelli’s BDDCS models.8

SI9

Table SI11. In silico PBC predictions of BDDCS classified data set (Vitamin B12, Propantheline Bromide,

Propoxyphene Napsylate, and Cilazaprilat were excluded due to missing fragments).7, 8

Drug BDDCS

class

Pred.

PBC* Drug

BDDCS

class

Pred.

PBC Drug

BDDCS

class

Pred.

PBC

Abacavir Sulfate I III Cerivastatin I I/III Escitalopram I I

Acarbose I I Cevimeline I I Esomeprazole I I

Acebutolol I III Chloral Hydrate I I Estradiol I I

Paracetamol I I Chlorambucil I II Eszopiclone I I

Acetohexamide I II Chloramphenicol I I Ethinylestradiol I I

Aspirin I I Chlordiazepoxide I II Ethosuximide I I

Alfacalcidol I I/II Chlormethiazole I I Everolimus I I/III

Alfuzosin I I Chlorpheniramine I I Famciclovir I I

Aliskiren I I/II Chlorpromazine I I Fentanyl I I

Alosetron I I Cilazapril I III Fesoterodine I IV

Alprazolam I I Clemastine I I Finasteride I I/II

Alprenolol I I Clindamycin I I Fludarabine 5'-

Monophosphate

I I

Ambrisentan I II Clobazam I II Fludrocortisone Acetate I I

Ambroxol I I Clomiphene Citrate I II Flunitrazepam I I

Aminopyrine I I Clomipramine I I Fluoxetine I I

Amitriptyline I I Clonazepam I II Flurazepam I I

Amlodipine I I Clorazepate I I Fluvastatin I III

Amoxapine I I Codeine I III Fluvoxamine I II

Anastrozole I II Colchicine I I Fosfluconazole I I/II

Antipyrine I I Cortisone I III Frovatriptan I I

Asenapine I II Cyclizine I I Galantamine I I

Atomoxetine I I Cyclobenzaprine I I Glibornuride I I/II

Azathioprine I II Cyclophosphamide I I Granisetron I I

Bambuterol I I Cyproheptadine I I Guanabenz I I

Benazepril I III Dabigatran Etexilate I I/II Hexobarbital I I

Benidipine I II Dantrolene I I/III Hydralazine Hydrochloride I I

Benserazide I I/III Darifenacin I I Hydrocodone I I

Benznidazole I II Debrisoquine I III Hydrocortisone I III

Bepridil I I Desipramine I I Hydromorphone I I

Beraprost I I Desmethyldiazepam I I Hydroxychloroquine Sulfate I I

Betamethasone I III Desogestrel I II Hydroxyzine I I

Betaxolol I I Dexamethasone I III Imidapril I III

Biperiden I III Dexmethylphenidate I I Imipramine I I

Bopindolol I I Dextromethorphan I I Indapamide I II

Bromazepam I I Diazepam I I Isoniazid I I

Bromocriptine I IV Diclofenac I I/II Isosorbide 2-Mononitrate I III

Bromperidol I II Dihydroquinidine I I Isosorbide 5-Mononitrate I III

Budesonide I I Dilevalol I I Isosorbide Dinitrate I III

Buflomedil I I Diltiazem I I Ivabradine I III

Buprenorphine I I Diphenhydramine I I Ivermectin I III

Bupropion I I Dolasetron I I Labetalol I III

Busulfan I I Dosulepin I I Letrozole I I/II

Butabarbital I II Doxazosin I I Levamisole I I

Butalbital I II Doxepin I I Levodopa (L-dopa) I III

Butorphanol I I Duloxetine I I Linezolid I I

Caffeine I I Eletriptan I I Lorazepam I I

Capecitabine I III Enalapril I III Lorcainide I I

Caprylidene I I/II Ergonovine I III Maprotiline I I

Carbidopa I III Ergotamine Tartrate I II/IV Maraviroc I I/II

SI10


Drug BDDCS

class

Pred

PBC Drug

BDDCS

class

Pred

PBC Drug

BDDCS

class

Pred

PBC

Melatonin I I Pimozide I II Theophylline I I

Melphalan I III Prazosin I I/III Thioguanine I I

Meperidine I I Prednisolone I III Thioridazine I I

Meprobamate I I Primaquine I I Ticlopidine I I

Mesna I III Prochlorperazine I I Tilidine; Tilidate I I

Methadone I I Proguanil I III Timolol I I

Methylergonovine I III Promazine I I Tinidazole I I

Methylphenidate I I Promethazine I I Tolterodine I I

Methylprednisolone I III Propranolol I I Toremifene I I

Metoprolol I I Propylthiouracil I I Tramadol I I

Metronidazole I I Protriptyline I I Tranylcypromine

Sulfate

I I

Mexiletine I I Pyrazinamide I I Triamcinolone I I/III

Mianserin I I Quetiapine I I Triamcinolone I I

Minocycline I I/III Quinacrine I I Triazolam I I

Minoxidil I I/III Quinidine I I Trifluoperazine I I

Mirtazapine I I Quinine I I Trihexyphenidyl I III

Misoprostol I I Rabeprazole I I Tropisetron I I

Molindone I I Ramelteon I I Valacyclovir I III

Morphine hydrochloride I III Ramipril I III Valganciclovir; Valcyte I I/III

Naloxone I III Reboxetine I I Valproic Acid I I

Naltrexone I III Reserpine I III Vardenafil I IV

Nefopam I I Ribavirin I III Venlafaxine I I

Nicotinic Acid I I Ridogrel I II Verapamil I III

Nicotinamide I I Riluzole I II Vitamin B6 I I

Nicardipine I III Rimantadine I I Vitamin D3 I I/II

Nicorandil I III Risperidone I IV Zidovudine I I

Nicotine I I Rivastigmine I I Zolmitriptan I III

Nitroglycerin I I/III Rizatriptan I I Zolpidem Tartrate I II

Norethindrone I II Ropinirole I I Zonisamide I I

Norgestimate I II Rosiglitazone I I Zopiclone I I

Norgestrel I I Roxatidine Acetate I III Acitretin II II

Nortriptyline I I Salicylic Acid I I Albendazole II II

Olmesartan Medoxomil I III Scopolamine I III Allopurinol II I

Omeprazole I I Secobarbital I II Altretamine II I/II

Ondansetron I I Selegiline I I Aminoglutethimide II I

Orphenadrine I I Sertraline I II Amiodarone II II

Oseltamivir Phosphate I I Sibutramine I I Amprenavir II IV

Oxprenolol I I Sildenafil I III Aprepitant II II

Oxybutynin I I Solifenacin I I Aripiprazole II II

Oxycodone I I Sparfloxacin I III Armodafinil II II

Oxymorphone I III Sumatriptan I III Artemether II II

P-Aminosalicylic Acid I IV Sunitinib I I Astemizole II II

Pantoprazole I I Tacrine I I Atazanavir Sulfate II IV

Paroxetine I II Tamoxifen I II Atorvastatin II II/IV

Pefloxacin I III Tamsulosin I I Bevantolol II I

Pentoxifylline I I Temazepam I I Bexarotene II II

Perindopril Erbumine I III Temocapril I I Bezafibrate II II

Phenobarbital I II Tenoxicam I II Bicalutamide II I

Phenylbutazone I II Terazosin I I Bosentan II IV

SI11


Drug BDDCS

class

Pred

PBC

Drug BDDCS

class

Pred

PBC

Drug BDDCS

class

Pred

PBC

Buspirone II III Flufenamic Acid II II Mycophenolate Mofetil II IV

Carbamazepine II II Flunarizine II II Nabumetone II I

Carvedilol II II Fluphenazine II III Nalidixic Acid II I

Cefditoren Pivoxil II IV Flurbiprofen II II Naproxen II I

Cefpodoxime Proxetil II II Flutamide II II Nateglinide II II

Celecoxib II II Folic Acid II IV Nefazodone II II

Chlorzoxazone II II Fosamprenavir II II/IV Nelfinavir II IV

Cilostazol II II Fosinopril II IV Nevirapine II II

Cinacalcet II II Gefitinib II II Nifedipine II II

Cisapride II III Gemfibrozil II II Nifurtimox II I

Citalopram II I Gliclazide II II Nilotinib II II

Clofazimine II II Glimepiride II II Nilvadipine II II

Clofibrate II I Glipizide II IV Nimesulide II II

Clopidogrel Bisulfate II II Glibenclamide II II Nimodipine II I

Clotrimazole II II Griseofulvin II I Nitrazepam II I

Clozapine II II Haloperidol II II Nitrendipine II II

Cyclosporine II IV Ibuprofen II I Norelgestromin II II

Cyproterone Acetate II II Idebenone II I Norethindrone Acetate II II

Danazol II II Iloperidone II IV Olanzapine II IV

Dapsone II I Imatinib Mesylate II IV Oxaprozin II II

Darunavir II IV Indinavir Sulfate II IV Oxatomide II II

Dasatinib II IV Indobufen II II Oxazepam II I

Delavirdine II II Indomethacin II II Oxcarbazepine II II

Desloratadine II I/II Indoramin II II Pentazocine II I

Diazoxide II II Irbesartan II II Perhexiline II I

Dicoumarol II II Isotretinoin II II Phenacetin II I

Diflunisal II II Isradipine II II Phenytoin II II

Diloxanide Furoate II II Itraconazole II II Pioglitazone II II

Dipyridamole II III Ketanserin II IV Piroxicam II II

Disulfiram II I Ketoconazole II I Pitavastatin II II

Domperidone II IV Ketoprofen II II Prasugrel II II

Donepezil II II Lamotrigine II II Prazepam II I/II

Dronabinol II II Lansoprazole II II Praziquantel II I

Dronedarone II II/IV Lapatinib Ditosylate II II Prednisone II III

Drospirenone II II Leflunomide II II Primidone II II

Ebastine II II Lofepramine II II Probenecid II I

Efavirenz II II Lopinavir II IV Probucol II II

Entacapone II IV Loratadine II II Progesterone II II

Eplerenone II I Losartan II IV Propafenone II I

Erlotinib Hydrochloride II II Lovastatin II II Quazepam II I/II

Estazolam II I Mebendazole II II Quinapril II I/II

Ethchlorvynol II I/II Mefenamic Acid II II Raloxifene; Keoxifene II III

Etodolac II II Mefloquine II I Raltegravir Potassium II II

Etoricoxib; Arcoxia II II Meloxicam II II Ranolazine II III

Etravirine II II Mercaptopurine II II Rifabutin II IV

Exemestane II II Mesalazine II III Rifampin II II

Ezetimibe II II Metaxalone II I Ritonavir II IV

Febuxostat II II Methaqualone II II Rofecoxib; Vioxx II II

Felodipine II II Modafinil II IV Rufinamide II II

Fenofibrate II II Montelukast II II Saquinavir II IV

SI12


Drug BDDCS

class

Pred

PBC Drug

BDDCS

class

Pred

PBC Drug

BDDCS

class

Pred

PBC

Sorafenib Tosylate II II Almotriptan III III Etoposide III III

Spironolactone II I Alvimopan III III Famotidine III III

Sulfamethoxazole II II Amantadine III I Fexofenadine III III

Sulfasalazine II IV Amiloride III IV Flecainide III I

Sulfinpyrazone II II Aminocaproic Acid III III Fluconazole III II

Sulindac II IV Amoxicillin III III Flucytosine III III

Tacrolimus II IV Ampicillin III III Fosfomycin

Tromethamine

III III

Tadalafil II I Atenolol III III Gabapentin III III

Tegaserod Maleate II III Atropine (Dl) III I Ganciclovir III III

Telithromycin II IV Azithromycin III IV Guanfacine III I/III

Telmisartan II II Baclofen III I Hydrochlorothiazide III III

Temozolomide II I/II Bendroflumethiazide III IV Hydroflumethiazide III III

Terbinafine II II Biotin (Vitamin H) III III Hydroxyurea III III

Terfenadine II IV Bisoprolol Fumarate III I Hyoscyamine; L-Atropine III I

Testolactone II II Bumetanide III IV Ibandronate III III

Testosterone II II Cadralazine III III Ketorolac III II

Tetrabenazine II I Captopril III III Lacosamide; Erlosamide III I

Thalidomide II II Carbenicillin III III Lamivudine III III

Thiabendazole II II Carteolol III III Leucovorin III III

Thyroxine II IV Cefaclor III III Levetiracetam III I

Tiagabine II III Cefadroxil III III Levocetirizine III III

Tiaprofenic Acid II II Cefamandole III IV Levofloxacin III III

Tipranavir II II Cefuroxime III III Lisinopril III III

Tizanidine II II Celiprolol III III Lomefloxacin III III

Tolazamide II II Cephalexin III III Loperamide III II

Tolbutamide II II Cephradine III III Loracarbef III III

Tolcapone II II Cetirizine III III Memantine III I

Tolfenamic Acid II II Chloroquine III I Metformin III III

Tolmetin II I Cimetidine III III Methazolamide III I

Tolvaptan II II Clarithromycin III IV Methotrexate III IV

Trandolapril II I/II Clavulanic Acid III III Methyldopa III III

Trazodone II II Clonidine III I Metoclopramide III I

Tretinoin II II Cycloserine III III Miglitol III III

Triamterene II II Dalfampridine III I Miglustat III III

Triclabendazole II II Demeclocycline III III Milnacipran III I

Trimipramine Maleate II I Desmopressin III III/IV Moxifloxacin III III

Ursodeoxycholic Acid II IV Desvenlafaxine III III Nadolol III III

Valdecoxib; Bextra II II Dicloxacillin III IV Naratriptan III III

Vitamin A (Retinol) II I Didanosine III III Neomycin B Sulfate III III

Voriconazole II II Digitoxin III IV Neostigmine III I

Warfarin II II Digoxin III IV Nizatidine III III

Zafirlukast II II Disopyramide III III Nystatin III IV

Zaleplon II II Dofetilide III III Ofloxacin III III

Zileuton II I Doxycycline III III Penicillamine III III

Ziprasidone II IV Emtricitabine III III Phenylethylmalonamide III III

Acamprosaic Acid III III Enalaprilat III III Phenylpropanolamine III I

Acrivastine III III Entecavir III III Pindolol III I

Adefovir Dipivoxil III I Erythromycin (Base) III III/IV Piperazine III I

Albuterol; Salbutamol III III Ethambutol III III Piracetam III I

Alendronate Sodium III III Etidronic Acid III III Pirenzepine III III

SI13


Drug BDDCS

class

Pred

PBC

Drug BDDCS

class

Pred

PBC

Drug BDDCS

class

Pred

PBC

Pramipexole III I Trimetazidine III III Enoxacin IV III

Pravastatin III IV Trimethoprim III I Eprosartan IV IV

Pregabalin III III Trospium Chloride III I/III Erythromycin Stearate IV IV

Procainamide III III Vancomycin III III/IV Felbamate IV III/IV

Pseudoephedrine III I Varenicline Tartrate III I Fleroxacin IV IV

Pyridostigmine III I Vigabatrin III III Furosemide IV IV

Pyrimethamine III II/IV Vitamin B1 III III Iopanoic Acid IV IV

Ranitidine III III Zalcitabine III I Lenalidomide IV III/IV

Risedronate III III Acetazolamide IV IV Levonorgestrel IV II

Ritodrine III III Acyclovir IV III/IV Medroxyprogesterone

Acetate

IV II/IV

Rolitetracycline III III Amisulpride IV III/IV Megestrol Acetate IV II/IV

Rosuvastatin III III Atovaquone IV II Niclosamide IV II

Saxagliptin III III Auranofin IV I Nitrofurantoin IV IV

Sitafloxacin III III Azapropazone;

Apazone

IV IV Norfloxacin IV III

Sitagliptin III I Candesartan IV II Orlistat IV II

Sotalol III III Cefdinir IV IV Paliperidone IV III/IV

Stavudine III I Cefixime IV IV Penicillin V IV IV

Sulpiride III III Cefpodoxime IV III Phenazopyridine

Hydrochloride

IV II

Talinolol III III Cefprozil IV III Rifaximin IV IV

Tenofovir Disoproxil III III Ceftibuten IV IV Roxithromycin IV IV

Terbutaline III III Chlorothiazide IV III/IV Sulfadiazine IV IV

Tetracycline III III Chlorthalidone IV IV Sulfamethizole IV IV

Tiludronate III III Cinoxacin IV IV Sulfisoxazole IV II

Tiotropium Bromide III III Ciprofloxacin IV III/IV Valsartan IV IV

Tocainide III I Clodronic Acid IV III/IV Vitamin B2 IV III

Topiramate III I Cloxacillin IV IV Torsemide; torasemide II II

Topotecan III III

*In silico PBC Prediction (inconclusive-PBC-classifications are due to being outliers of applicability domain of stand-alone

models)

Table SI12. Computational assignments of PBC classes for Compounds in Different Drug Discovery Stages

Data*** Total

Predicted

PBC

Class I

Predicted

PBC

Class II

Predicted

PBC

Class III

Predicted

PBC

Class IV

Non-Conclusive-Classification

I/II I/III II/IV III/IV NC*

×100 (%) Count**

Drugsa 1541 0.45 0.21 0.20 0.08 45 10 19 8 2

Phase 1b 703 0.20 0.50 0.18 0.05 26 7 7 5 0

Phase 2b 908 0.27 0.47 0.15 0.06 16 3 18 7 0

Phase 3b 270 0.42 0.32 0.12 0.07 4 3 7 2 0

W6c 28786 0.15 0.63 0.07 0.10 263 205 671 130 19

W9c 4994 0.22 0.62 0.07 0.05 81 3 85 74 8

*NC: non-classified compounds (neither solubility nor permeability are conclusively classified) due to being outliers of

model Applicability Domains; ** Data are represented as number of compounds; ***these data were precisely predicted by

BDDCS based in silico models developed by Broccatelli et al.8;

adrugs data set including both oral and non-oral drugs;

bdrugs that accessed clinical phases;

9 cmedicinal chemistry compounds tested for at least one target and having micromolar

(W6) or nanomolar (W9) bioactivity.9-11

SI14

REFERENCE

1. Powers, D. M. W. Evaluation: From Precision, Recall and F-Factor to ROC, Informedness, Markedness &

Correlation; School of Informatics and Engineering, Flinders University Adelaide, Australia, SIE-07-001, December, 2007;

pp 1-24. At:

2. Chen, G.; Zheng, S.; Luo, X.; Shen, J.; Zhu, W.; Liu, H.; Gui, C.; Zhang, J.; Zheng, M.; Puah, C. M.; Chen, K.; Jiang,

H. Focused combinatorial library design based on structural diversity, druglikeness and binding affinity score. J. Comb.

Chem. 2005, 7 (3), 398-406.

3. Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. A Knowledge-Based Approach in Designing Combinatorial or

Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug

Databases. J. Comb. Chem. 1999, 1, 55-68.

4. Congreve, M.; Carr, R.; Murray, C.; Jhoti, H. A rule of three for fragment – based lead discovery? . Drug Discov.

Today 2003, 8, 876 – 877.

5. Zamora, I.; Oprea, T. I.; Ungell, A. L., Prediction of oral drug permeability. In Rational Approaches to Drug Design,

Holtje, H. D.; Sippl, W., Eds. Prous Science Press: Barcelona, Spain, 2001; pp 271-280.

6. Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines

immediate-release, solid oral dosage forms; Technical Report Series No. 937; 40th; WHO Expert Committee on

Specification for Pharmaceutical Preparations, WHO Technical Report Series, No. 937, 2006; pp 391-461. At:

http://www.who.int/medicines/publications/essentialmedicines/en/index.html. Accessed 3 March 2012

7. Benet, L. Z.; Broccatelli, F.; Oprea, T. I. BDDCS Applied to Over 900 Drugs. AAPS J. 2011, 13 (4), 519-547.

8. Broccatelli, F.; Cruciani, G.; Benet, L. Z.; Oprea, T. I. BDDCS class prediction for new molecular entities. Mol.

Pharmaceutics 2012, 9 (3), 570-580.

9. Oprea, T. I.; Allu, T. K.; Fara, D. C.; Rad, R. F.; Ostopovici, L.; Bologa, C. G. Lead-like, drug-like or “Pub-like”:

how different are they? J. Comput. Aided Mol. Des. 2007, 21, 113−119.

10. Olah, . ad, . . Ostopovici, . Bor , . adaruga, . adaruga, D. oldovan, . ulias, . racec, .

Oprea, T. I., WOMBAT and WOMBAT-PK: Bioactivity databases for lead and drug discovery. In Chemical Biology: From

Small Molecules to Systems Biology and Drug Design, Schreiber, S. L. K.; Kapoor, T. M.; Wess, G., Eds. Wiley-VCH:

Weinheim, Germany, 2007 p 780−786.

11. WOMBAT-PK 2010, available from Sunset Molecular Discovery LLC, New Mexico, USA

(http://www.sunsetmolecular.com).

http://www.who.int/medicines/publications/essentialmedicines/en/index.html

http://www.sunsetmolecular.com)/

provisional classification and in silico study of ... · provisional classification and in silico...

Documents