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PHARMACOKINETICS OF SSRI ANTIDEPRESSANTS

Alphonse Poklis, Ph.D., ABFTProfessor, Pathology

Pharmacology & ToxicologyChemistry & Forensic Science

School of MedicineVirginia Commonwealth UniversityRichmond, VA 23298-0165

Selective Serotonin Reuptake Inhibitors (SSRI)

Citalopram Citalopram ((CelexaCelexa, , CipramilCipramil, , SeropramSeropram))EscitalopramEscitalopram ((LexaproLexapro))

DuloxetineDuloxetine ((CymbaltaCymbalta))Fluoxetine (Prozac)Fluoxetine (Prozac)FluvoxamineFluvoxamine ((LuvoxLuvox))Paroxetine Paroxetine ((PaxilPaxil))Sertraline Sertraline (Zoloft)(Zoloft)Venlafaxine Venlafaxine ((EffexorEffexor))

Drug # Cases % Case Mode Range Units

Blood Alcohol 2230 76.3 0.12 0.01 - 0.40 gm %THC 345 12.0 0.001 <0.001 - 0.026 mg/LTHC-Acid 442 15.0 0.024 0.002 - 0.280 mg/LAlprazolam 108 3.7 0.038 0.020 - 0.672 mg/LDiazepam 79 2.7 0.39 0.020 - 1.70 mg/LNordiazepam 91 3.1 0.16 0.050 - 2.10 mg/LCocaine 31 1.1 0.005 0.002 - 0.071 mg/LBenzoylecgonine 79 2.7 0.16 <0.100 - 3.2 mg/LButalbital 71 2.4 1.0 0.500 - 38.9 mg/LHydrocodone 44 1.5 0.020 0.020 - 202 mg/LOxycodone 40 1.4 0.067 0.024 - >0.500 mg/LCarisoprodol 36 1.2 0.020 1.0 - 30.0 mg/LMeprobamate 38 1.3 0.020 2.1 - 50.0 mg/LPhencyclidine [PCP] 37 1.3 0.017 0.013 - 0.089 mg/LMorphine 32 1.1 0.030 0.020 - >0.500 mg/L

Trazodone/Olanzapine/Paroxetinein Blood Extract – DB-5

9.00 10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00

2000000

4000000

6000000

8000000

1e+07

1.2e+07

1.4e+07

Time-->

Abundance

TIC: 1429.D

M-C

PPal

phap

rodi

ne

paro

xetin

e

olan

zapi

ne

trazo

done

Toxicology Findings, 43 yr Woman:

DrugDrug blood,mg/Lblood,mg/L Liver, mg/KgLiver, mg/KgHydrocodoneHydrocodone 0.090.09MethadoneMethadone 1.21.2 1212BupropionBupropion 0.40.4FluoxetineFluoxetine 0.70.7 4040AmitriptylineAmitriptyline 0.60.6 2626NortriptylineNortriptyline 1.41.4 3636QuetiapineQuetiapine <.1<.1 44PromethazinePromethazine 0.20.2 11DiazepamDiazepam 0.10.1NordiazepamNordiazepam 0.30.3DoxylamineDoxylamine 0.090.09 0.10.1

Antidepressant Drugs:Pharmacokinetic ConsiderationLarge Apparent volume of distributionLarge Apparent volume of distributionChiral Chiral drugsdrugsActive metabolitesActive metabolitesBiotransformationBiotransformation

Interactions with CYP450 Interactions with CYP450 isoenzymesisoenzymes

DISPOSITION OF DRUGS

The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).

Site of Action

Dosage EffectsPlasmaConcen.

Pharmacokinetics Pharmacodynamics

02

46

810

1214

0 5 10 15 20

TIME (hours)

Plas

ma

conc

entr

atio

nDrug Plasma Profile

Bound Free Free Bound

LOCUS OF ACTION“RECEPTORS”

TISSUE RESERVOIRS

SYSTEMIC CIRCULATION

Free Drug

Bound Drug

ABSORPTION EXCRETION

BIOTRANSFORMATION



TISSUE RESERVOIRS


Free Drug

Bound Drug


BIOTRANSFORMATION

KA KE

KM

Pharmacokinetic DataBioavailability(%)Bioavailability(%)Volume of distribution (L/Kg)Volume of distribution (L/Kg)Bound in plasma (%)Bound in plasma (%)Distribution Ratio of [plasma]/[blood]Distribution Ratio of [plasma]/[blood]Plasma halfPlasma half--life (hr)life (hr)Clearance (mL/min/Kg)Clearance (mL/min/Kg)Urinary excretion (%)Urinary excretion (%)

Pharmacokinetic Data

Single dose peak plasma concentrationSingle dose peak plasma concentrationEffective steady state plasma concentrationEffective steady state plasma concentrationToxic plasma concentrationToxic plasma concentrationLife threatening or lethal blood Life threatening or lethal blood concentrationconcentration

Dose

Destroyedin gut

Notabsorbed

Destroyed by gut wall

Destroyedby liver

tosystemiccirculation

Bioavailability

Bioavailability

Definition: the fraction of the administered dose reaching the systemic circulation

for i.v.: 100%for non i.v.: ranges from 0 to 100%

e.g. lidocaine bioavailability 35% due to destruction in gastric acid and liver metabolism

First Pass Effect

05

1020

50

100

0 5 10 15 20

TIME (hours)

Log

Plas

ma

conc

entr

atio

n

IV

Oral

Bioavailability = (AUC) Oral(AUC) IV

Drugs appear to distribute in the body as if it were a single compartment. The magnitude of the drug’s

distribution is given by the apparent volume of distribution (Vd).

Amount of drug in bodyConcentration in Plasma

Vd =

Apparent Volume of Distribution

Vd = Dose/C0

Gradient Between Drug in Blood and Drug in Other Tissues & FluidsVd = 1 L/Kg, in 70 Kg man = 70LIf 70mg dose, then 70mg/70L/Kg = 1 mg/L in bloodDistribution Total drug in blood/total drug in body tissues = 4mg/66mg

Vd = 10 L/Kg, in 70 Kg man = 700LIf 70mg dose, then 70mg/700L/Kg = 0.1 mg/L in bloodDistribution Total drug in blood/total drug body tissues =

0.4mg/69.6mg

Drug L/Kg L/70 kgSulfisoxazole 0.16 11.2 Phenytoin 0.63 44.1 Phenobarbital 0.55 38.5 Diazepam 2.4 168 Digoxin 7 490

Examples of apparent Vd’s for some drugs

Hemodialysis

Rate of toxicant removal related toRate of toxicant removal related toBlood flow through Blood flow through dialyzerdialyzerDialysate Dialysate flow rateflow rateDrug solubilityDrug solubilityPermeability of membranes, surface >2MPermeability of membranes, surface >2M22

DisadvantagesDisadvantagesInfectionsInfectionsBlood clots, Blood clots, hematomashematomasComplex apparatus, skill personnelComplex apparatus, skill personnel

Dialysis Clearance

Dialysis clearance = E x B x SDialysis clearance = E x B x SWhereWhere

E = extraction ratio = Ca E = extraction ratio = Ca –– CvCv/Ca/CaWhere; Ca is concentration of toxicant in Where; Ca is concentration of toxicant in arterial bloodarterial bloodCv Cv is concentration of toxicant in venous is concentration of toxicant in venous bloodblood

B = blood flow (300 mL/min)B = blood flow (300 mL/min)S = serum factor (1S = serum factor (1--hematocrithematocrit) )

Hemodialysis Pharmacokinetics

Dialyzer Dialyzer flow rate, 300 mL/minflow rate, 300 mL/minIf Extraction ratio = 1, to totally clear blood If Extraction ratio = 1, to totally clear blood (5000 mL) of agent where;(5000 mL) of agent where;

Ke Ke = 300 mL/min /5000 mL= 300 mL/min /5000 mLKe Ke = 0.06/min (~6%)= 0.06/min (~6%)T1/2 = 0.0693 / 0.06/ min = 11.6minT1/2 = 0.0693 / 0.06/ min = 11.6minTotal removal = 5 x T1/2 = 58 minTotal removal = 5 x T1/2 = 58 min

Hemodialysis PharmacokineticsClearance of Methanol

Dialyzer Dialyzer flow rate, 300 mL/minflow rate, 300 mL/minIf Extraction ratio = 1, to totally clear blood (5000 If Extraction ratio = 1, to totally clear blood (5000 mL) of agent where;mL) of agent where;

Vd Vd = 0.6L/Kg, 70Kg man= 0.6L/Kg, 70Kg manKe Ke = 300 mL/min /42000 mL= 300 mL/min /42000 mLKe Ke = 0.007/min (~0.7%)= 0.007/min (~0.7%)T1/2 = 0.0693 / 0.007/ min = 99minT1/2 = 0.0693 / 0.007/ min = 99minTotal removal = 5 x T1/2 = 495 min (~8 hours)Total removal = 5 x T1/2 = 495 min (~8 hours)

Hemodialysis PharmacokineticsClearance of Phenytoin


Vd Vd = 0.8L/Kg, 70Kg man= 0.8L/Kg, 70Kg manKe Ke = 300 mL/min /56000 mL= 300 mL/min /56000 mLKe Ke = 0.005/min (~0.5%)= 0.005/min (~0.5%)T1/2 = 0.0693 / 0.005/ min = 138minT1/2 = 0.0693 / 0.005/ min = 138minTotal removal = 5 x T1/2 = 690 min (~11.5 hr)Total removal = 5 x T1/2 = 690 min (~11.5 hr)

Hemodialysis PharmacokineticsClearance of AmitriptylineDialyzer Dialyzer flow rate, 300 mL/minflow rate, 300 mL/minIf Extraction ratio = 1, to totally clear blood (5000 If Extraction ratio = 1, to totally clear blood (5000 mL) of agent where;mL) of agent where;

Vd Vd = 10L/Kg, 70Kg man= 10L/Kg, 70Kg manKe Ke = 300 mL/min /700,000 mL (700L)= 300 mL/min /700,000 mL (700L)Ke Ke = 0.0004/min (~0.04%)= 0.0004/min (~0.04%)T1/2 = 0.0693 / 0.0004/ min = 173min (~2.9 hr)T1/2 = 0.0693 / 0.0004/ min = 173min (~2.9 hr)Total removal = 5 x T1/2 = 866 min (~14.4 hr)Total removal = 5 x T1/2 = 866 min (~14.4 hr)

Hemodialysis PharmacokineticsClearance of Fluoxetine


Vd Vd = 30L/Kg, 70Kg man= 30L/Kg, 70Kg manKe Ke = 300 mL/min /2,100,000 mL (2,100L)= 300 mL/min /2,100,000 mL (2,100L)Ke Ke = 0.00014/min (~0.014%)= 0.00014/min (~0.014%)T1/2 = 0.0693 / 0.00014/ min = 495min (~8.3 hr)T1/2 = 0.0693 / 0.00014/ min = 495min (~8.3 hr)Total removal = 5 x T1/2 = 2,475 min (~41.25 hr)Total removal = 5 x T1/2 = 2,475 min (~41.25 hr)



TISSUE RESERVOIRS


Free Drug

Bound Drug

IV injection EXCRETION

BIOTRANSFORMATION

KE

KM

Ct = C0 . e – KEt

lnCt = lnC0 – KE t

logCt = logC0 – KEt 2.303

dC/dt = – kC

y = b – mx

dC/dt related C

First Order Elimination

T im e

Log

Plas

ma

Con

cent

ratio

n

0 1 2 3 4 5 61

1 0

1 0 0

1 0 0 0

1 0 0 0 0

C 0

D is tr ib u tio n eq u ilib r iu m

E lim in a tio n o n ly

D is tr ib u tio n a n d E lim in a tio n

Plasma Concentration Profile after a Single I.V. Injection

Time

Log

Plas

ma

Con

cent

ratio

n

0 1 2 3 4 5 61

10

100

1000

10000 First Order Elimination

logCt = logC0 – Ket/ 2.303

Slope = -KE

logC0

Plasma Elimination Rate Constant

KE is the fraction of drug continuously removed from plasma (blood) per unit time (hr).

Thus; if KE = -0.25/hr, the plasma drug concentration is continuouslydeclining by ~25%

Plasma Elimination Rate Constant

KE = the sum of all rate processes that remove the drug from plasma.

KE = KM1 + KM2 + KU + Kothers

Where; KM1 = rate of formation of metabolite 1

KM2 = rate of formation of metabolite 2KU = rate of urinary excretionKothers = rate of other processes, ex sweat,

Fluvoxamine Metabolism

F3

NO

NH2

OCH3

F3

NO

OH

OCH3

F3

NOH

OCH3

F3

NO

NH2

COOH

Overmars et al European J Drug Pharmacok 8:269-280,1983

Km1

Km2Km3

KIDNEYfiltrationsecretion(reabsorption)

LIVERmetabolismsecretion

LUNGSexhalation

OTHERSmother's milk

sweat, saliva etc.

Eliminationof drugs from the body

MAJOR

MINOR

lnCt = lnC0 – KEt

The plasma half-lifeis the time for the plasma concentration to decline to half the original concentration

T1/2= 0.693/KE

When: lnCt = lnCt1/2lnC0 = lnC0

t = t1/2

Time

Log

Plas

ma

Con

cent

ratio

n

0 1 2 3 4 5 61

50

100

1000

10000

Plasma Half-Life

Cp/2

Cp

t1 t2t1/2 = 4 hrs

First Order Elimination

Clearance:Clearance: volume of plasma cleared of volume of plasma cleared of drug per unit time.drug per unit time.

Clearance = Clearance = Rate of eliminationRate of eliminationPlasma concentrationPlasma concentration

Rate of elimination = KE x Amount in bodyRate of elimination = CL x [Plasma]

Therefore,KE x Dose = CL x [plasma]

KE = CL/Vd

VdKE= CL

0.693 Vd/ t1/2 = CL

Plasma Clearance

Plasma Clearance

Clearance is used to determine iv infusion rates

Css CL = dosing rate

Example, lidocaine CL = 11 mL/min/Kg, in 70 Kg man = 0.8 L/min/KgCss = 3mg/LDosing rate = 0.8L/min/Kg x 3mg/L = 2.4 mg/min



TISSUE RESERVOIRS


Free Drug

Bound Drug


BIOTRANSFORMATION

KA Ke

KM

Multiple dosing

On continuous steady administration of a drug, On continuous steady administration of a drug, plasma concentration will rise fast at first then plasma concentration will rise fast at first then more slowly and reach a plateau, where:more slowly and reach a plateau, where:

rate ofrate of administration administration = rate of = rate of eliminationelimination

ieie. steady state is reached.. steady state is reached.

0

1

2

4

8

16

32

64

0 5 10 15 20 25 30

Time

Plas

ma

Con

cent

ratio

n Steady State Concentration

Steady State Plasma ConcentrationsObtained after dosing for 5 halfObtained after dosing for 5 half--liveslivesAfter drug administration is stopped, After drug administration is stopped, requires 5 halfrequires 5 half--lives to decline to zerolives to decline to zero

Steady State Plasma Concentrations

Dose after dose after 1 half-life11stst 100100 505022ndnd 150150 757533rdrd 175175 888844thth 188188 949455thth 194194 979766thth 197197 9898

Css = F (dose)/ Vd Ke T

Css = 1.44 F (dose) t1/2/ Vd T

Css = Plasma Steady State ConcentrationF = BioavailabilityVd = Volume of distributionKe = Plasma elimination rate constantT = Dosage intervalt1/2 = Plasma half-life

Pharmacokinetic parameters

Volume of distribution Volume of distribution V = DOSE / CV = DOSE / C00

Plasma clearancePlasma clearance ClCl = K= KEE ..VVdd

plasma halfplasma half--life life t1/2t1/2 = 0.693 / K= 0.693 / KEE

BioavailabilityBioavailability (AUC)(AUC)xx / (AUC)/ (AUC)iviv

Daily Dose (mg/kg)

Plas

ma

Dru

gC

once

ntra

tion

(mg/

L)

0 5 10 150

10

20

30

40

50

60

Variability in Drug Metabolism

Antidepressant Drugs:Metabolism Consideration

The metabolism rate for antidepressants can vary The metabolism rate for antidepressants can vary due to cytochrome p450 due to cytochrome p450 isoenzymes isoenzymes Genetic polymorphisms exist that may classify a Genetic polymorphisms exist that may classify a person as a “poor metabolizer” of a given p450 person as a “poor metabolizer” of a given p450 enzyme. (i.e. CYP 2D6, CYP 2C19)enzyme. (i.e. CYP 2D6, CYP 2C19)Certain drugs may inhibit the production of a Certain drugs may inhibit the production of a particular enzyme or may compete with an particular enzyme or may compete with an enzyme, thus making an individual a poor enzyme, thus making an individual a poor metabolizermetabolizer

Cytochrome P-450 Cycle

[P-450 (Fe+3)]

[P-450 (Fe+2)] [RH]

[P-450 (Fe+3)] [RH][P-450 (Fe+3)] [RH]

O

[P-450 (Fe+2)] [RH]O2=

[P-450 (Fe+2)] [RH]O2

2H+

H 2O

R-OH or epoxideRH substrate

e-via NADPHplus a reductase enzyme

Oxygen

e-via NADPHor NADHplus a reductase enzyme

Cytochrome P-450: Oxidative

Structural diversity due toStructural diversity due toNonspecificityNonspecificityIsozymesIsozymes -- multiple forms of an enzymemultiple forms of an enzyme

Enzymes are “inducible” by various chemicalsEnzymes are “inducible” by various chemicalsExposure increases the rate of enzyme Exposure increases the rate of enzyme productionproduction

Cytochrome P-450: Oxidative

IsozymesIsozymes differ in protein structurediffer in protein structure

Different amino acid sequencesDifferent amino acid sequencesProduce different 3Produce different 3--D structuresD structuresDrug bound to the protein portionDrug bound to the protein portion

Remember: Remember: All activated oxygen chemistry occurs at the All activated oxygen chemistry occurs at the iron center iron center hemeheme with oxygen transfer to the with oxygen transfer to the protein bound substrateprotein bound substrate

Polymorphism in Clinical Pharmacology

Drug metabolism enzymesDrug metabolism enzymesCytochromeCytochrome P450's (CYP)P450's (CYP)NAD(p)H NAD(p)H quinonequinone oxidoreductase oxidoreductase NN--acetyl transferase (NAT) acetyl transferase (NAT) Thiopurine methyltransferase (TPMT)Thiopurine methyltransferase (TPMT)

Receptor proteinsReceptor proteinsαα22--Adrenergic receptorAdrenergic receptorDopamine D3Dopamine D3--receptorreceptor

Genetic Polymorphism

Structural variations of a gene (Allele) Structural variations of a gene (Allele) MendelianMendelian inheritance inheritance

Homozygous: Homozygous: Two common or two Two common or two variant allelesvariant allelesHeterozygous: Heterozygous: One common and one One common and one variant allele variant allele Recessive: Recessive: Must be homozygous to reveal Must be homozygous to reveal phenotypephenotypeDominant: Dominant: Heterozygous genotype Heterozygous genotype displays variant phenotypedisplays variant phenotype

Mechanisms of polymorphism

Single nucleotideSingle nucleotideCoding region Coding region NonNon--coding region coding region

Regulatory sequencesRegulatory sequencesIntron Intron

Gene deletion, duplication Gene deletion, duplication

Cytochrome P450 Nomenclature

CYP’sCYP’s that have 40% or greater sequence that have 40% or greater sequence homology are classified as the same familyhomology are classified as the same familyEnzymes with 55% or greater sequence Enzymes with 55% or greater sequence homology are classified in the same homology are classified in the same subfamilysubfamilyCYP2D6 is the abbreviation for the CYP in CYP2D6 is the abbreviation for the CYP in family 2, subfamily D, gene product 6family 2, subfamily D, gene product 6

Nomenclature

Cytochrome P450 2 D 6 *4

Superfamily

Family

Subfamily

Isoenzyme

Allele Variant

Hepatic Cytochrome P450 Content

1A218%

2A65%

3A40%

2B61%

2C24%

2D63%

'2E19%

Cytochrome P450 Isoenzymes

It has been reported that for drugs that undergo It has been reported that for drugs that undergo oxidative biotransformationoxidative biotransformation

50% metabolized by CYP 3A3/450% metabolized by CYP 3A3/430% metabolized by CYP 2D630% metabolized by CYP 2D610% metabolized by CYP 2C9/1010% metabolized by CYP 2C9/104% metabolized by CYP 1A24% metabolized by CYP 1A22% metabolized by CYP 2C192% metabolized by CYP 2C192% metabolized by CYP 2E12% metabolized by CYP 2E1

Cytochrome P450 2D6

Polymorphism Polymorphism –– none or have less than normal none or have less than normal amountsamounts

55--10% of Caucasians10% of Caucasians–– poor poor metabolizersmetabolizers~1% of Asian ~1% of Asian –– poor poor metabolizersmetabolizers

Many important hydroxylation reactionsMany important hydroxylation reactionsantidepressants, antidepressants, antipsychoticsantipsychotics, analgesics, & , analgesics, & cardiovascular drugs cardiovascular drugs

2D6 can be inhibited by drugs2D6 can be inhibited by drugsNot necessary for drug to be substrate to inhibit Not necessary for drug to be substrate to inhibit P450 P450

AutoinhibitionAutoinhibition

Cytochrome P450 2D6Substrates

SSRI SSRI TCA’sTCA’sAntipsychotics Antipsychotics BetaBeta--Blockers Blockers CodeineCodeineTramadolTramadolDextromethophanDextromethophanEncainideEncainideFlecainideFlecainide

InhibitorsInhibitorsSSRI ClomipramineBupropionCimetidineChlorpromazine, CocaineMethadone, DoxorubicinHaloperidolQuinidine

SSRI InhibitorsCytochrome P450 2D6

Weak to Moderate InhibitorsWeak to Moderate InhibitorsCitalopramCitalopramDuloxetineDuloxetineFluvoxamineFluvoxamineSertralineSertraline

Potent InhibitorsPotent InhibitorsFluoxetine Fluoxetine NorfluoxetineNorfluoxetineParoxetine Paroxetine

Cytochrome P450 3A4Substrates

AnalgesicsAntiarrhythmicsAntidepressants-SSRIsBenzodiazepinesCalcium antagonistsCocaineLovastatinMacrolide antibioticsOmeprezole

InhibitorsSSRIsCimetidineDiltiazemGrapefruit juiceKetoconazole Verapamil

Inducers of Cytochrome P450 3A4

BarbituratesBarbituratesCarbamazepineCarbamazepineGlucocorticoidsGlucocorticoidsPhenytoinPhenytoinRifampinRifampinSt. John’s St. John’s wortwort

SSRI InbibitorsCytochrome P450 3A4

Weak Inhibitor CitalpramFluoxetineParoxetineSertraline

Potent InhibitorNorfluoxetineFluvoxamine

00

MichaelisMichaelis--Menten Menten KineticsKinetics

VV

[S][S]

KKmm

Vmax

V = Vmax ( [S] / [S] + Km)

If [S] >>> Km, V = Vmax

If Km >>> [S], V = constant [S]

Reciprocal MichaelisMichaelis--MentenMenten

1/V

1/[S]

Intercept y-axis = 1/V

Slope = Km/Vmax

Intercept onx-axis = -1/ Km

1/V = 1/Vmax + Km/Vmax X 1/[S]

1/V = 1/Vmax + Km/Vmax(1 + 1/K1)(1/[S])

Competitive Enzyme InhibitionCompetitive Enzyme Inhibition

Where, K1 is the dissociation constant of the enzyme-inhibitor complex

In the presence of an inhibitor, the slope increases by the factor (1 + 1/K1)

Km is increasedVmax is unaltered

Competitive Enzyme Inhibition

1/V

1/[S]

Competitive inhibitor

No inhibitor present

Factors Complicating Interpretation of Postmortem Blood Concentrations

Large individual variations in pharmacokinetic Large individual variations in pharmacokinetic parameters in therapeutic situationsparameters in therapeutic situationsAlterations in pharmacokinetics in overdoseAlterations in pharmacokinetics in overdose

Saturation of biotransformation & eliminationSaturation of biotransformation & eliminationNonNon--equilibrium distribution equilibrium distribution

“postmortem release” of tissue bound drugs into “postmortem release” of tissue bound drugs into blood after deathblood after death

A. Poklis, Internat Assoc Forensic Sci, Vancouver, 1987

Postmortem Blood to Calculate Dose

If Vd is high, then CbVd does not = Dose

If Vd is low, then Vd = Dose/C0

Selective Serotonin Reuptake Inhibitors (SSRI)

CitalopramCitalopram ((CelexaCelexa, , CipramilCipramil, , SeropramSeropram))EscitalopramEscitalopram ((LexaproLexapro®®))

DuloxetineDuloxetine ((CymbaltaCymbalta))Fluoxetine (Prozac)Fluoxetine (Prozac)FluvoxamineFluvoxamine ((LuvoxLuvox))Paroxetine Paroxetine ((PaxilPaxil))Sertraline Sertraline (Zoloft)(Zoloft)Venlafaxine Venlafaxine ((EffexorEffexor))

Daily Dose (mg/kg)

Plas

ma

Dru

gC

once

ntra

tion

(mg/

L)

0 5 10 150

10

20

30

40

50

60

Variability in Pharmacokinetics

SSRI Metabolism

Inhibit metabolism of other drugsInhibit metabolism of other drugsAutoinhibitionAutoinhibition: :

inhibit their own metabolisminhibit their own metabolismnonnon--linear relationship between dose and linear relationship between dose and blood concentrationblood concentrationincrease blood halfincrease blood half--life with increasing life with increasing doses doses

SSRI’s That Exhibit Autoinhibition

Fluoxetine & Fluoxetine & norfluoxetinenorfluoxetineFluvoxamine Fluvoxamine Paroxetine Paroxetine

Citalopram

O

F

N CH3

CH3

CitalopramDosage: 20Dosage: 20--60 mg/day60 mg/dayBioavailability 80%Bioavailability 80%FbFb: 0.80: 0.80Time to Peak: ~4 hrTime to Peak: ~4 hrVdVd: 12: 12--16 L/kg16 L/kgt t ½½: 25: 25--35 hr35 hrTime to Steady State: 6Time to Steady State: 6--7 days7 days

Citalopram Biotransformation

Desmethycitalopram CYP3A4 / CYP2D6 / CYP 2C19 Didesmethycitalopram, CYP 2D6

Active Metabolite:Desmethycitalopram (25-50%f parent)Didesmethycitalopram (10% of Parent)

% excreted in urine: citalopram 12%

desmethycitalopram 5%

CitalopamVery weak inhibitorVery weak inhibitor

CYP 3A4CYP 3A4CYP 2B6CYP 2B6CYP 2C9CYP 2C9CYP 2D6CYP 2D6CYP 2C19 CYP 2C19

Elderly, increased halfElderly, increased half--lifelifeHepatic disease Hepatic disease –– little effectlittle effectRenal disease Renal disease –– little effectlittle effect

O

F

N CH3

CH3

O

F

N CH3

H

O

F

N H

H

desmethylcitalopram

N-didesmethylcitalopram

CITALOPRAM METABOLISM

Citalopram & Quetiapine

10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

1100000

1200000

1300000

1400000

1500000

Time-->

Abundance

TIC: 10607.D

Alp

rapr

odin

e

Cita

lopr

am

Que

tiapi

ne M

etab

olite

Que

tiapi

ne

9.50 10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00

50000

100000

150000

200000

250000

300000

350000

400000

450000

500000

Time-->

Abundance

TIC: 6061.D

Istd

Caf

fein

e

Cita

lopr

amD

iaze

pam

Nor

fluox

etin

e

Nor

tript

ylin

e

Tram

adol

O-D

esm

ethl

yram

adol

Citalopam & Others

Citalopram Serum ValuesSingleSingle-- and multipleand multiple--doses both produce doses both produce linear and dose proportional effects linear and dose proportional effects within the 10within the 10--60 mg/day prescription60 mg/day prescriptionTherapeutic valueTherapeutic value

citalopram citalopram 5050--100 ng/mL100 ng/mLdesmethycitalopram desmethycitalopram 1515--40 ng/mL40 ng/mL

Toxic Concentration > 1,000 (?)Toxic Concentration > 1,000 (?)

Citalopram Isomers

ON CH3

CH3

F F

ON CH3

CH3

“S” and “R” isomers (“S” and “R” isomers (racemicracemic mixture)mixture)“S” isomer 2“S” isomer 2--4 times SSRI then “R”4 times SSRI then “R”

Citalopram Enantiomers in Femoral Blood, 53 Postmortem Cases

CitalopramCitalopramMean S isomer 1.53 ug/mL, SD = 3.57Mean S isomer 1.53 ug/mL, SD = 3.57Mean R isomer 1.72 ug/mL, SD = 3.58Mean R isomer 1.72 ug/mL, SD = 3.58S/R = 0.67, SD 0.25S/R = 0.67, SD 0.25

DesmethylcitalopramDesmethylcitalopramMean S isomer 0.14 ug/mL, SD = 0.21Mean S isomer 0.14 ug/mL, SD = 0.21Mean R isomer 0.20 ug/mL, SD = 0.22Mean R isomer 0.20 ug/mL, SD = 0.22S/R = 0.68, SD 0.20S/R = 0.68, SD 0.20

Holmgren et al J. Anal. Toxicol. 26:94-104,2004

Escitalopram“S” isomer “S” isomer citalopramcitalopram))10 mg = 2010 mg = 20--40 mg 40 mg citalopramcitalopram

Escitalopram CYP 450

R & S isomers R & S isomers metabolizedmetabolized by same P450by same P450Substrate:Substrate:

CYP 2C19CYP 2C19CYP 3A4CYP 3A4CYP 2C19CYP 2C19

Weak Weak inhibitor: inhibitor: CYP 2D6CYP 2D6

Duloxetine

O

NCH3

HS

DuloxetineDosage: 40Dosage: 40--120 mg/day120 mg/dayBioavailability ?Bioavailability ?FbFb: 95%: 95%Time to Peak: ~4 hrTime to Peak: ~4 hrVdVd: Mean 27 L/Kg (13: Mean 27 L/Kg (13--50 L/kg)50 L/kg)t t ½½: 6 : 6 --19 hr19 hrTime to Steady State: 3Time to Steady State: 3--5 days5 days

Duloxetine Elimination Biotransformation

Extensive ring hydroxylationO-Methylation Glucuronide & sulfate conjugation

Plasma metabolites as glucuronides:4-hydroxy-duloxetine5,6-hydroxy-duloxetine6-hydroxy-5-methoxy duloxetine 4,6-dihydroxy-duloxetine

Radioactivity excreted in urine: 72% in 13 daysRadioactivity excreted in feces: 18% in 13 days

Duloxetine Metabolism

Substrate:Substrate:CYP 2D6CYP 2D6CYP 1A2CYP 1A2

Bioavailability reduced by 1/3 in smokersBioavailability reduced by 1/3 in smokersElderly, no significant change in halfElderly, no significant change in half--lifelifeModerate inhibitorModerate inhibitor

CYP 2D6CYP 2D6

Duloxetine Plasma Metabolites

O

NCH3

HS

O

NCH3

HS

OH

O

NCH3

HS

OHOH

O

NCH3

HS

OHO CH3

O

NCH3

HS

OH

OH

6-hydroxyCatechol

4,6-hydroxy 5-hydroxy-6-methoxy

Lanz et al. Drug Metab. Dispos. 31:1142,2003

Duloxetine Urine Metabolites

O

NCH3

HS

OSO3

O CH3

O

NCH3

HS

OGlucuronide

11 hydroxylated and hydroxy-methoxy metabolites Excreted as glucuronide and sulfate conjugates

13 – 21%10 – 16%

Duloxetine Serum Steady-State Trough Values

Twelve healthy adult menTwelve healthy adult menDose 20 mg bidDose 20 mg bid

12ng/mL (2 12ng/mL (2 –– 12ng/mL) 12ng/mL) Dose 30 mg bidDose 30 mg bid

20 ng/mL (10 20 ng/mL (10 –– 48 ng/mL)48 ng/mL)Dose 40 mg bidDose 40 mg bid

30 ng/mL ( 1230 ng/mL ( 12-- 40 ng/mL)40 ng/mL)Generally trough serum values > 5 ng/mL predicts Generally trough serum values > 5 ng/mL predicts sustained inhibition of 5sustained inhibition of 5--HT reuptake.HT reuptake.

Sharma et al J Clin. Pharmacol. 40:161,2000

Fluoxetine

F3C

O NCH3

H

FluoxetineDosage: 20Dosage: 20--80 mg/day80 mg/dayFbFb: 0.94: 0.94Time to Peak: 6Time to Peak: 6--8 hr8 hrVdVd: 20: 20--42 L/kg42 L/kgTime to Steady State: 1 week Time to Steady State: 1 week –– monthmonth% excreted as parent in urine: <10%% excreted as parent in urine: <10%

Fluoxetine Stereoisomers

F3C

O NCH3

H

H NCH3

H

HO

F3C

Similar SSRI activity

Norfluoxetine Stereoisomers

F3C

O NH

H

H

NH

HO

F3C

H

S >>>> R in SSRI activity

FLUOXETINE METABOLISMBiotransformation to Biotransformation to norfluoxetine norfluoxetine is is mediated by CYP 2D6mediated by CYP 2D67% of population reduced CYP 2D6 activity7% of population reduced CYP 2D6 activity

S isomer metabolized slower to S isomer metabolized slower to norfluoxetinenorfluoxetine, results in higher Flu/, results in higher Flu/norflunorfluR isomer normal rateR isomer normal rateAt steadyAt steady--state concentration of the 4 state concentration of the 4 parentparent--metabolite isomers equalmetabolite isomers equalNo pharmacological differenceNo pharmacological difference

Fluoxetine CYP 450Substrate:Substrate:

CYP1A2CYP1A2CYP 2B6CYP 2B6CYP 2C8/9CYP 2C8/9CYP 2C19CYP 2C19CYP 2D6CYP 2D6CYP 2E1CYP 2E1CYP 3A4CYP 3A4

Fluoxetine CYP 450Moderate to severe inhibitor: Moderate to severe inhibitor:

CYP 1A2CYP 1A2CYP CYP 2B62B6CYP 2C8/9CYP 2C8/9CYP 2C19CYP 2C19CYP CYP 2D62D6CYP 3A/4CYP 3A/4

NorfluoxetineNorfluoxetine: Inhibitor of 3A3/4 (potent): Inhibitor of 3A3/4 (potent)

F3C

O NCH3

H

F3C

O NH

H

F3C

OH

FLUOXETINE METABOLISM

Norfluoxetine

Trifluoromethylphenol

10.0010.5011.0011.5012.0012.5013.0013.5014.0014.5015.0015.50

200000

400000

600000

800000

1000000

1200000

1400000

1600000

1800000

2000000

2200000

2400000

2600000

2800000

3000000

3200000

Time-->

Abundance

TIC: 9130.D

ISTD

fluox

etin

eno

rflu

oxet

ine

doxy

lam

ine

dext

rom

etho

rpha

n

oxyc

odon

e

Fent

anyl

Fluoxetine / Norfluoxetine

Fluoxetine Half-lifet t ½½: 24: 24--72 hr (dose dependent)72 hr (dose dependent)

short term doses 1short term doses 1-- 3 days3 dayslong term doses 4 long term doses 4 -- 6 days6 days

t t ½½: : norfluoxetine norfluoxetine (1(1stst order)order)short term doses 4 short term doses 4 -- 16 days16 dayslong term doses 4 long term doses 4 -- 16 days16 days

FLUOXETINE METABOLISM

HalfHalf--life increased with hepatic diseaselife increased with hepatic diseaseHalfHalf--live not influenced bylive not influenced by

Decreased Decreased renel renel functionfunctionEderlyEderlyPediatric patientsPediatric patients

Fluoxetine Serum ValuesSingle 40 mg dose = 15Single 40 mg dose = 15--55 ng/mL55 ng/mL40 mg/day for one week40 mg/day for one week

Fluoxetine 91 Fluoxetine 91 –– 300 ng/mL300 ng/mLNorfluoxetine Norfluoxetine 72 72 ––260 ng/mL 260 ng/mL

40 mg/day for one month40 mg/day for one monthFluoxetine 47 Fluoxetine 47 -- 470 ng/mL470 ng/mLNorfluoxetineNorfluoxetine 52 52 -- 450 ng/mL 450 ng/mL

Fluoxetine Serum ValuesLarge variation in peak and trough concentrations Large variation in peak and trough concentrations dependent upondependent upon

DoseDoseDosage regimentDosage regimentCoCo--administration of other drugsadministration of other drugs

Therapeutic values Therapeutic values fluoxetinefluoxetine, ~ 100 , ~ 100 -- 500 ng/mL500 ng/mLnorfluoxetinenorfluoxetine, ~100 , ~100 -- 450 ng/mL450 ng/mL

Toxic ConcentrationsToxic ConcentrationsFluoxetine >1,500 ng/mL (?)Fluoxetine >1,500 ng/mL (?)

DesipramineDosage: 25Dosage: 25--300 mg/day300 mg/day

FbFb: 0.95 : 0.95 Time to Peak: 3Time to Peak: 3--6 hr6 hrVdVd: 22: 22--59 L/kg59 L/kgt t ½½: 12: 12--54 hr54 hrTime to Steady State: 2Time to Steady State: 2--8 days8 days

DESIPRAMINE METABOLISM

N

NHCH3

NH

N

NHCH3

OH

N

NHCH3

OHN

NH2

10-OH-desipramine

2-OH-desipraminenordesipramine

iminodibenzyl

CYP2D6

CYP3A4

Metabolism of Desipramine

Mediated by CYP1A2, CYP3A4, CYP2C19Mediated by CYP1A2, CYP3A4, CYP2C19Desipramine Desipramine 1010--OHOH--DesipramineDesipramine

Mediated by CYP2D6Mediated by CYP2D6Desipramine Desipramine 22--OHOH--DesipramineDesipramine

Fluoxetine/Desipramine

Chronic administrationChronic administration20 mg/day20 mg/day fluoxetinefluoxetine50 mg/day desipramine50 mg/day desipramine

Desipramine plasma values Desipramine plasma values increased 4Xincreased 4Xwith concomitantwith concomitant fluoxetine fluoxetine Desipramine plasma values Desipramine plasma values still elevated 3 still elevated 3 weeksweeks after after fluoxetine fluoxetine discontinueddiscontinued

Fluvoxamine

F3

NO

NH2

OCH3

FluvoxamineDosage: 100Dosage: 100--200 mg/day200 mg/dayFbFb: 0.77: 0.77Time to Peak: 2 Time to Peak: 2 --8 hr8 hrVdVd: 25 L/kg: 25 L/kgt t ½½: 8: 8--24 hr (dose dependent >200mg)24 hr (dose dependent >200mg)Time to Steady State: 2Time to Steady State: 2--4 days4 days

Fluvoxamine Elimination Extensively biotransformed Extensively biotransformed

Oxidation, Oxidation, deaminationdeaminationNN--O cleavageO cleavageNN--acetylated acetylated

% excreted as parent in urine: ~3%% excreted as parent in urine: ~3%Therapeutic ConcentrationTherapeutic Concentration

~200 ng/mL ~200 ng/mL Toxic ConcentrationToxic Concentration

>2,500 ng/mL (?)>2,500 ng/mL (?)

Fluvoxamine CYP 450Substrate: Substrate:

CYP1A2CYP1A2CYPCYP 2D62D6

Moderate to Severe Inhibitor: Moderate to Severe Inhibitor: CYP 1A2CYP 1A2CYP 2B6CYP 2B6CYP 2C8/9CYP 2C8/9CYP 2C19CYP 2C19CYP 2D6CYP 2D6CYP 3A/4CYP 3A/4

Fluvoxamine Metabolism

F3

NO

NH2

OCH3

F3

NO

OH

OCH3

F3

NOH

OCH3

F3

NO

NH2

COOH

Overmars et al European J Drug Pharmacok 8:269-280,1983

Fluvoxamine Metabolism, cont.

F3

NO

OHCOOH

F3

NO

OH

OCH3

F3

NO COOH

OCH3

F3

NOH

OCH3

F3

NOH

COOH

F3

NO

NH2

COOH

F3

NO

COOHCOOH

F3

OCOOH

10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00

50000

100000

150000

200000

250000

300000

350000

400000

450000

500000

550000

600000

650000

700000

Time-->

Abundance

TIC: 15763.D

m-C

CP

mep

erid

ine

norm

eper

idin

eIS

TDC

affe

ine

Fluv

oxam

ine

Traz

adon

e

prom

etha

zine

Fluvoxamine / Meperidine / Trazodone

Fluvoxamine Serum Values

Single dose 100 mgSingle dose 100 mgPeak 31Peak 31--87 ng/mL87 ng/mL

Therapeutic ConcentrationTherapeutic Concentration~200 ng/mL ~200 ng/mL

Toxic ConcentrationToxic Concentration>2,500 ng/mL (?)>2,500 ng/mL (?)

Paroxetine

OO

O

N

F

ParoxetineDosage: 10Dosage: 10--50 mg/day50 mg/dayFbFb: 0.95: 0.95Time to Peak: 3Time to Peak: 3--8 hr8 hrVdVd: 5: 5--28 L/kg28 L/kgTime to Steady State: ~ 1 week

Paroxetine EliminationCYP 2D6 Polymorphism Extensively biotransformed

ring oxidative cleavage

t t ½½: 7: 7--37 hr (dose dependent) 37 hr (dose dependent) fast metfast met, , ~ 16 hr ~ 16 hr slow metslow met (7% population), ~ (7% population), ~ 41 hr41 hr

Parent excreted in urine: <1%

Paroxetine & CYP 450Substrate: Substrate: CYP2D6 CYP2D6 Moderate to serve InhibitorModerate to serve Inhibitor

CYP1A2 CYP1A2 CYP CYP 2B62B6CYP 2C8/9CYP 2C8/9CYP 2C19CYP 2C19CYP 2D6 CYP 2D6 CYP CYP 3A/43A/4

PAROXETINE METABOLISM

OO

O

N

F

O H

O

N

F

O C H3

O HO

O

N

F

C H3

O H

N

F

Paroxetine /Amitriptyline

10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00 14.50 15.00

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

110000

120000

130000

140000

150000

160000

170000

180000

190000

Time-->

Abundance

TIC: 5282.D

alphaprodine

amitriptyline

nortriptyline

paroxetine

9.50 10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00 14.50 15.00

50000

100000

150000

200000

250000

300000

350000

400000

450000

Time-->

Abundance

TIC: 6024.D

Istd

Met

hado

ne

Chl

orph

enira

min

e

Paro

xetin

e

Paroxetine / Methadone

Paroxetine Serum Values• Single 20 mg dose peak

• 1 – 33 ng/mL • 30mg/day, steady-state (15 subjects)*

• Peak, average 62 ng/mL• Trough, aveage 31 ng/mL

• Toxic Concentration• >300 ng/mL (?)

Tasker et al Acta Psych. Scand.,Suppl. 350:152,1989.

Sertraline

NC H 3

C l

C l

H

SertralineDosage: 50Dosage: 50--200 mg/day200 mg/dayFbFb: 0.99: 0.99Time to Peak: 6Time to Peak: 6--8 hr8 hrVdVd: 70 L/kg: 70 L/kgHalfHalf--life: life:

SertralineSertraline 2222--36 hr36 hrNorsertraline Norsertraline 60 60 ––70 hr 70 hr

Time to Steady State: 4Time to Steady State: 4--6 days6 days

Sertraline EliminationBiotransformed Biotransformed

NN--dealkylationdealkylationring hydroxylationring hydroxylation

Active Metabolite: Active Metabolite: norsertraline norsertraline (20%f parent)(20%f parent)Metabolism decreasedMetabolism decreased

Hepatic diseaseHepatic diseaseElderly patientsElderly patients

% of parent excreted in urine: <0.2%% of parent excreted in urine: <0.2%

Sertraline & CYP450 IsozymesModerate Inhibitor at high dosesModerate Inhibitor at high doses

CYP 2C19CYP 2C19CYP 3A3CYP 3A3CYP 3A4 CYP 3A4 CYP CYP 2B62B6CYP CYP 2C192C19

Weak InhibitorWeak InhibitorCYP 2C8/9 CYP 2C8/9 CYP 1A2CYP 1A2CYP 2D6 CYP 2D6

SERTRALINE METABOLISM

NCH3

Cl

Cl

HN

H

Cl

Cl

H

Norsertraline

CYP 3A4

10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00 14.50

50000

100000

150000

200000

250000

300000

350000

400000

450000

500000

550000

600000

650000

700000

Time-->

Abundance

TIC: 6476.D

Phth

alat

e

Istd

Serr

talin

e

Nor

serr

talin

e

Sertraline in Blood Extract DB-5

Methadone / Sertralinein Blood Extract DB-5

9.50 10.00 10.50 11.00 11.50 12.00 12.50 13.00

200000

400000

600000

800000

1000000

1200000

1400000

1600000

1800000

2000000

2200000

2400000

Time-->

Abundance

TIC: 1507.DA

lpha

prod

ine,

IS

met

hado

ne sertr

alin

eno

rser

tralin

e

Sertraline Serum ValuesSingle dose average peakSingle dose average peak

50 mg50 mg dose, ~10 ng/mLdose, ~10 ng/mL100 mg dose, 16 ng/mL100 mg dose, 16 ng/mL200 mg dose, 56 ng/mL 200 mg dose, 56 ng/mL

Steady State average (range)Steady State average (range)50mg dose, 32 ng/mL (20 50mg dose, 32 ng/mL (20 –– 48)48)100 mg dose, 91 ng/mL (40 100 mg dose, 91 ng/mL (40 ––187)187)200 mg dose, 206 ng/mL (99 200 mg dose, 206 ng/mL (99 –– 309) 309)

N ON

F

N

N

O

CH3

N ON

F

N

N

O

CH3

OH

N OHO

F

N

N

O

CH3

N

N

O

CH3

COOH

N ON

F

N

N

O

CH3

OH

Risperidone Metabolism

2-Hydroxyrisperidone

9-Hydroxyrisperidone

Risperidone Metabolism

N ON

F

N

N

O

CH3

N ON

F

N

N

O

CH3

OH

9-HO-risperidone , equipotent

CYP2D6Lesser CYP3A4

Risperidone PharmacokineticsCYP2D6 Polymorphism

Plasma halfPlasma half--lifelifeSlowSlow

RisperidoneRisperidone ~20 hr~20 hr99--HOHO--risperidonerisperidone ~30 hr ~30 hr

FastFast

RisperidoneRisperidone ~3 hr~3 hr99--HOHO--risperidonerisperidone ~21 hr~21 hr

Sertraline & RisperidonePatients receiving 4 Patients receiving 4 –– 6mg/day, at 2 months 6mg/day, at 2 months average plasma concentrationaverage plasma concentration

Risperidone Risperidone + 9+ 9--hydroxy risperidonehydroxy risperidone53 +/53 +/-- 12 ng/mL12 ng/mL

Sertraline Sertraline added 50mg/day after 2 monthsadded 50mg/day after 2 monthsRisperidoneRisperidone + 9+ 9--hydroxy risperidonehydroxy risperidone55 +/55 +/-- 10 ng/mL10 ng/mL

Sertraline Sertraline range 22 range 22 –– 43 ng/mL43 ng/mL

Spina et al Ther Drug Monit 26:386,2004

Venlafaxine

OCH3

OH

NCH3

CH3

VenlafaxineDosage: 75Dosage: 75--225 mg/day225 mg/dayFbFb: 0.99: 0.99Time to Peak: 2Time to Peak: 2--4 hr4 hrVdVd: 4: 4--12 L/kg12 L/kgt t ½½: : venlafaxinevenlafaxine 33--7 hr 7 hr

oo--methyl metabolite 9methyl metabolite 9--13 hr13 hrTime to Steady State: 1Time to Steady State: 1--3 days3 days

Venlafaxine EliminationBiotransformed Biotransformed -- polymorphism polymorphism

NN--dealkylationdealkylationOO--dealkylationdealkylation

Active Metabolite: OActive Metabolite: O--desmethylvenlafaxine desmethylvenlafaxine % excreted in urine: % excreted in urine:

parent, 5%parent, 5%OO--methylvenlafaxinemethylvenlafaxine, 29, 29--48%48%NN--didesmethylvenlafaxinedidesmethylvenlafaxine, 6, 6--19%19%NN--desmethylvenlafaxinedesmethylvenlafaxine, 0.2, 0.2--8%%8%%

Venlafaxine CYP 450Substrate: Substrate:

CYP 2C8/9CYP 2C8/9CYP 2C19CYP 2C19CYP 2D6CYP 2D6CYP CYP 3A/43A/4

Inhibitor: Inhibitor: CYP 2B6CYP 2B6CYP 2D6CYP 2D6CYP 3A/4CYP 3A/4

VENLAFAXINE METABOLISM

OCH3

OH

NCH3

CH3

OCH3

OH

NCH3

H

OH

OH

NCH3

CH3

N-desmethylvenlafaxine

O-desmethylvenlafaxine

OCH3

OH

NH

H

N,N-didesmethylvenlafaxine

10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00 14.50

100000

200000

300000

400000

500000

600000

700000

800000

900000

1000000

1100000

Time-->

Abundance

TIC: 8811.D

ISTD

venl

afax

ine

diaz

epam

nord

iaze

pam

n-de

smet

hylv

enla

faxi

ne

o-de

smet

hylv

enla

faxi

ne

Venlafaxine & Metabolites

Met ?

Venlafaxine Steady-State Serum ValueSteady state 150 mg/day, Steady state 150 mg/day, 50mg 50mg tidtid

venlafaxinevenlafaxine, peak , peak 194194 ng/mL, SD 67 ng/mLng/mL, SD 67 ng/mLvenlafaxinevenlafaxine, trough 52 ng/mL, SD 38 ng/mL, trough 52 ng/mL, SD 38 ng/mLOO--desmethyldesmethyl, peak , peak 313313 ng/mL, SD 118 ng/mLng/mL, SD 118 ng/mLOO--desmethyldesmethyl, trough 185 ng/mL, SD 67 ng/mL, trough 185 ng/mL, SD 67 ng/mL

Steady state 150 mg/day, Steady state 150 mg/day, 75mg bid75mg bidvenlafaxinevenlafaxine, peak , peak 189 189 ng/mL, SD 54 ng/mLng/mL, SD 54 ng/mLvenlafaxinevenlafaxine, trough 56 ng/mL, SD 31 ng/mL, trough 56 ng/mL, SD 31 ng/mLOO--desmethyldesmethyl peak peak 308308 ng/mL, SD 121 ng/mLng/mL, SD 121 ng/mLOO--desmethyldesmethyl, trough 194 ng/mL, SD 75 ng/mL, trough 194 ng/mL, SD 75 ng/mL

Troy et al, J Clin. Pharmacol 35:404-409,1995

Venlafaxine Serum ValueSingle 50 mg doseSingle 50 mg dose aveageaveage

venlafaxinevenlafaxine, 70 ng/mL (2.2 hr), 70 ng/mL (2.2 hr)OO--desmethylvenlafaxinedesmethylvenlafaxine, 106 ng/mL (3.9 hr), 106 ng/mL (3.9 hr)

Toxic concentrationsToxic concentrations>5,000 ng/mL (?)>5,000 ng/mL (?)

Postmortem blood concentrationsPostmortem blood concentrationsAve. 56Ave. 56 mgLmgL (6 (6 ––89 mg/L)89 mg/L)

R.C. Baselt, Disposition Toxic Drugs & Chemicals in Man, 6ed, 2002

[email protected]

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