duoc dong hoc - ths. nguyen thi mai hoang

TS. ng Nguyn oan Trang

I CNG V DC NG HC

BM Dc lm sng

Mc tiu

1. Trnh by c cc khi nim tng qut v cc giai on

hp thu, phn b, chuyn ho, thi tr

2. Nu c nh ngha v cch tnh mt s thng s dc

ng hc c bn

3. Xc nh c vai tr ca cc thng s dc ng hc

trong tnh ton liu dng v la chn phng thc tr liu

4. Xc nh c cc yu t nh hng n cc thng s

dc ng hc.

ThucC th

Dc lc hc(Pharmacodynamics, PD)

Dc ng hc(Pharmacokinetics, PK)

Dc ng hc (Pharmacokinetics) l mn hc nghin cu

v s phn ca mt thuc khi c a vo c th, thng qua s thay i theo thi gian ca cc hnh thi khc

nhau (hp thu, phn b, chuyn ha, o thi) ca thucy (Thrapie,1978).

nh ngha dc ng hc

ng dng dc ng hc

- Gip pht trin, la chn v s dng cc sn phm thuc

- Gip xc nh thuc s v tr tc ng vi hm lng bao

nhiu v ko di bao lu

- Gip tnh c liu dng thuc ph hp cho tng c th

- Gip theo di tr liu

- Gip hiu chnh liu nhng c a c bit (ngi gi, tr em,

ngi suy gan, thn,)

- Gip nh gi v tin lng c hiu qu v c tnh ca

thuc

Dc ng hc(Pharmacokinetics)

Hp thu(Absorption)

Phn b(Distribution)

Chuyn ho(Metabolism)

Thi tr(Excretion)

Thuc dngng ung

Drug Absorption Thuc trongmu

M

Sn phmthi tr

Sn phmchuyn ho

Hp thuThi tr

Chuyn ho

Phn b

S ADMEThuc dng

ng IV

Thuc dngng SC, IM

GIAI ON HP THU

Bao gm ton b cc hin tng gip thuc tht s vo c th

bt u t ni c chn a thuc vo

Cc thng s dc ng c bn ca s hp thu

Sinh kh dng (SKD) (Bioavailability)

Biu th t l (%) v vn tc ca thuc vo n vng tun hon

dng cn tc dng (dng nguyn thy v cht chuyn ho c

hot tnh)

GIAI ON HP THU

- Phn kh dng F (%): c nh gi trong mi tng

quan vi dng bo ch quy chiu

- Vn tc hp thu: o lng bi

Cmax: nng ti a trong huyt tng

Tmax: thi gian t nng ti a

Ka: hng s ca vn tc hp thu

GIAI ON HP THU

SKD c th c tnh ton bi din tch di ng cong

(AUC-Area Under the Curve)

AUC: biu din s bin thin ca nng thuc trong mu

theo thi gian hay tng trng cho lng thuc vo c

vng tun hon dng cn hot tnh sau mt thi gian t.

(Tmax)

(Cmax)

AUC

GIAI ON HP THU

AUC

GIAI ON HP THU

Tnh AUC nh th no?

GIAI ON HP THU

SKD tuyt i (so vi dng bo ch chun l dd tim IV)

F =AUC ng ung (PO)

AUC ng tnh mch (IV)x

Liu IV

Liu PO

SKD tng i (so vi dng bo ch mu chn la, cng

liu v cng ng cho thuc)

F =AUC dng th nghim (PO)

AUC dng mu (PO)

(1)

(2)

GIAI ON HP THU

Mt s v d v ng dng cc thng s dc ng hc ca

s hp thu

1. nh gi kh nng p ng yu cu iu tr da vo SKD

tuyt i:

SKD tuyt i > 50%: cho tc dng ton thn

SKD tuyt i > 80%: lng thuc vo mu xp x ng tnh

mch

SKD tuyt i < 50%: kh t yu cu cho tc dng ton thn,

cho tc ng ti ng tiu ho nu dng ng ung.

GIAI ON HP THU

Mt s v d v ng dng cc thng s dc ng hc ca

s hp thu

2. nh gi tng ng sinh hc (bioequivalence) da vo SKD

tng i

nh ngha tng ng sinh hc: Hai ch phm cng hot cht, cng liu

dng, cng ng a thuc c xem l tng ng sinh hc

(bioequivalence) khi cc s liu trung bnh ca AUC0-t, AUC0-, Cmax; Tmax

thu c t thuc th dao ng mc cho php (thng trong khong 80%

- 125%) so vi thuc la chn th nghim (thuc i chng)

(Lu : cc gi tr logarit ho. Nu cha logarit ho, khong dao ng cho

php l 80 120%)

GIAI ON HP THU

GIAI ON HP THU

Hai dng bo ch ca cng 1 hot cht c cng SKD nhng khng

tng ng sinh hc

GIAI ON HP THU

Thng thng, quy nh v tng ng sinh hc ch bt buc p

dng i vi AUC. i vi cc thuc c phm vi tr liu hp, TSH

cn bt buc p dng i vi c 3 thng s (AUC, Tmax, Cmax)

GIAI ON HP THU

MTC

MEC

A

B

C

GIAI ON HP THU

Cc yu t nh hng n s hp thu

- Dng bo ch

- Hot cht

- C ch lm trng d dy ca h tiu ho

- Lng mu rut

- Hiu ng vt qua ln u (first pass effect)

- Cc yu t khc (thc n, tui tc, tng tc thuc, bnh

l,)

GIAI ON HP THU

Hiu ng vt qua ln u (first pass effect)

L s mt mt ca thuc bi cc bin i sinh hc trc khi

vo n h thng tun hon chung khi thuc tip xc vi c

quan c chc nng trong s bin dng (hay ph hu) n.

GIAI ON HP THU

GIAI ON PHN B

S phn b thuc l ton b cc hin tng chi phi s phn

chia hot cht trong c th. N c thc hin bng hnh

thc vn chuyn th ng bi mu v cc c ch chuyn

ch qua mng t bo.

Thuc dngng ung

Drug Absorption Thuc trongmu

M

Sn phmthi tr

Sn phmchuyn ho

Hp thuThi tr

Chuyn ho

Phn b

S ADMEThuc dng

ng IV

Thuc dngng SC, IM

GIAI ON PHN B

S phn b mu

Hot cht Mu

Thuc-Protein

Thuc dng t do

Phn tn vo m

Cho tc ng

Lc qua cu thn

Albumin (50-60% protein

huyt tng), globulin,

alpha-1-glycoprotein acid,

lipoprotein

GIAI ON PHN B

Dc ng hc 1 ngn

Vd: aminoglycosides

GIAI ON PHN B

Dc ng hc 2 ngn

GIAI ON PHN B

Dc ng hc 2 ngn

Vd: Vancomycin

GIAI ON PHN B

S phn b m

Cc yu t nh hng n s phn b thuc m:

- Kh nng gn kt ca thuc v protein ca m

Thuc-protein huyt tng >> Thuc-protein m

Thuc-protein huyt tng

GIAI ON PHN B

S phn b m

Cc yu t nh hng n s phn b thuc m:

- S ti mu cc c quan

- i lc c bit ca thuc i vi mt s m.

Vd: cc aminosides tp trung m thn v tai trong

GIAI ON PHN B

Cc thng s dc ng c bn ca s phn b

Th tch phn b biu kin (Vd): biu th th tch cn phi

c ton b lng thuc c a vo c th phn b

nng bng nng trong huyt tng.

Vd thng c tnh ton sn v c th s dng trn nhng

i tng khng c nhng bt thng v sinh l hoc khng

c bnh l nng trn gan, thn.

GIAI ON PHN B

Vd =D x F

Cp

D: Dose (Liu) (g/mg)

F: Sinh kh dng (%)

Cp: Nng thuc trong

huyt tng (g/L, mg/mL)

(3a)

Loading dose = Vd x Cp

F(3b)

QU TRNH CHUYN HO (BIN I SINH HC)

Gip cc thuc tan trong lipid tr nn phn cc hn, nh bi

tit d dng hn dng thuc ban u.

Thuc Cht chuyn ho

C hot tnh V hot

V hot (tin cht) C hot tnh (c tnh)

3

2

1



Giai on I Giai on II

Kiu phn ng Oxy ho, kh, thu phn Lin hp

Loi tc ng caphn ng

Bin i hay hnh thnh 1

nhm chc ho hc

Gn thm mt thnh

phn thng l c

cc

Cc men tc ngtrong phn ng

Monooxygenase ph thuc

Cytochrome P450 (CYP

450)

Transferase



Cc enzyme chnh trong h thng cytochrome P450 tham gia

chuyn ho thuc


Cc yu t nh hng n s chuyn ho thuc gan

- Yu t di truyn

Vd: isoniazidAcetyl ho chm

Acetyl ho nhanh

- Yu t tui tc

Vd: tch t nordiazepam do thiu men chuyn ho tr s

sinh



- S cm ng men gan

Lm tng s tng hp cc men chuyn ho thuc tng s

chuyn ho v lm gim hot tnh thuc (nu cht chuyn ho

v hot)

Cc cht gy cm ng men: phenobarbital, phenytoin,

rifampicin, ru, thuc l,

TNG TC THUC



V d v s cm ng men gan:

Rifampicin cm ng men chuyn ho thuc trnh thai gim

tc dng thuc trnh thai

Dng thuc ng loi barbiturate lu di s c hin tng dung

np thuc v barbiturate cm ng men chuyn ho ca chnh

n.



- S c ch men gan

Hai cht chuyn ho bi cng 1 enzyme c th tng tranh vi

nhau. Cht c i lc mnh vi men s l cht c u tin chuyn

ho.

TNG TC THUC

Cc cht gy c ch men: cimetidine, chloramphenicol, isoniazid,

dicoumarol, ketoconazole, disulfiram, allopurinol,



V d v s c ch men gan:

- Cimetidine c ch men chuyn ho theophylline tng nng

theophylline c th dn n c tnh.

- Dicoumarol c ch men chuyn ho phenytoin lm tng c

tnh ca phenytoin.

Ty theo cc c tnh l ha m mt thuc c o thi ra khi

c th theo nhng phng cch khc nhau:

- o thi di dng khng bin i qua thn hay mt (trng

hp thuc d tan trong nc)

- o thi di dng b bin i (trng hp thuc d tan trong

lipid).

GIAI ON THI TR (BI TIT)


Cc thng s dc ng c bn ca s thi tr

thanh lc (Clearance) (Cl): biu th kh nng ca mt c

quan no ca c th (gan, thn) lc sch thuc ra khi

huyt tng khi mu tun hon qua c quan (ml/pht hoc

ml/gi).

ClT = ClR + CLER

ClT : thanh lc ton phn

ClR : thanh lc thn

ClER: thanh lc ngoi thn

(4)



Vd: Theophylin chuyn ho ch yu gan vi Clgan 0.6 ml/pht/kg

Trn bn 50 kg: Clgan 0.6 ml/pht/kg x 50kg = 30ml/pht

Mi pht c khong 30 ml huyt tng c gan lc sch theophylin.



Thi gian bn thi (Half-life ) (T1/2): l thi gian cn thit

nng thuc trong huyt tng gim i mt na.



k hay ke : hng s tc thi tr



Khi tim tnh mch (trng hp dc ng hc 1 ngn):

C = C0 x e-kt

Khi C = x C0 th t = T1/2

T1/2 = 0.693

k(5)



S ln T1/2 Lng thuc c thi tr (%)1 502 753 884 945 976 987 99

Sau 7xT1/2: Thuc c xem nh bi xut hon ton khi c th.


Trng thi n nh (steady state)


Trng thi n nh (steady state)

Sau 5 xT1/2: Thuc t trng thi cn bng


Mi lin h gia cc thng s dc ng hc

ClT =AUC0-

Nu dng thuc bng ng tim tnh mch

DD: Dose (Liu)

Nu dng thuc bng ng ung

(6)

ClT =AUC0-

D x F (7)



Cl =Cp

e: Tc thanh lc (mg/pht)

trng thi n nh (steady state) : Cp = Css

(8)

Cp: Nng thuc trong huyt tng

(mg/pht)

Cl =Css

(9) Css: Nng thuc trong huyt

tng trng thi n nh

(mg/pht)

e



Css = inf / Cl hay inf = Cl x Css (10)

Nu thuc c truyn ng tnh mch lin tc (IV infusion),

trng thi n nh tc thi tr = tc truyn

Nu thuc c ung hay tim IV gin on, trng thi n nh

(~5 T1/2):

Css =Cl x t

F x D(11a)

e = inf)

hay Maintenance dose =Css x Cl x t

F (11b)



T1/2 =0,693 x Vd

Cl

Lin quan gia T1/2, Cl v Vd

Lin quan gia T1/2 v khong cch a thuc vo ( dose

interval) ()

ln

0,693x T1/2

C0Ct

(12)

(13)


T1/2 v khong cch gia cc ln dng thuc

- T1/2 ngn (vi pht - 4 gi): dng thuc nhiu liu lp li

- T1/2 = 4 gi vi gi: thng dng 2 liu cch nhau 12gi.

- T1/2 > 12 gi: thng ch cn 1 liu/ngy

GIAI ON THI TR

Dc ng hc bc 0 (zero-order pharmacokinetics)

(dc ng hc khng tuyn tnh)

Khi vn tc thi tr khng ph thuc vo nng thuc

trong c th.

GIAI ON THI TR

Dc ng hc bc 1 (first-order pharmacokinetics)

(dc ng hc tuyn tnh)

Khi vn tc thi tr ph thuc vo nng thuc trong

c th.

TM TT CC THNG S DC NG HC C BN

Dc ng hc(Pharmacokinetics)

Hp thu(Absorption)

Phn b(Distribution)

Chuyn ho(Metabolism)

Thi tr(Excretion)

F

AUCTmaxCmax

Vd

ClT1/2kee (k)

D

Cp

Css

(Loading dose (liu tn cng), maintenance dose ( liu duytr))

CC YU T C TH NH HNG N CC THNG S DC

NG HC

Cc yu t sinh l

- pH d dy, c ch lm trng d dy

- pH mu, pH nc tiu

- Lu lng mu rut, lu lng lc cu thn

- Protein huyt tng

- Tui tc

Cc yu t sinh l

- Tui tc

Phng trnh Rowland gip hiu chnh liu dng trn tr em v ngi

cao tui

Liu tr em = Din tch ton c th (m2) x Liu ngi ln

1,8

Liu ngi cao tui = (140 tui) x Din tch ton c th (m2)

153x Liu ng

ln

Cc yu t bnh l

- Suy thn

- Gim lc cu thn

- Gim t l thuc gn vi protein huyt tng

Liu (-) S ln dng thuc

(-) Liu S ln dng thuc

Liu S ln dng thuc

Cc yu t bnh l

- Suy thn

Cng thc Crockroft-Gault nh gi chc nng thn:

ClCr (ml/pht)= (140 tui) x Cn nng (kg)

72 x Creatinin huyt thanh (mg/dL)(x 0,85 (n))

Cc yu t bnh l

Cc yu t bnh l

- Suy gan

- Gim lu lng mu n gan

- Gim kh nng chuyn ho ca t bo gan

- Gim nng albumin hay tng nng bilirubin trong

mu

Cc yu t bnh l

- Suy gan

- Nn chn nhng thuc o thi ch yu qua thn hoc lin hp

glucuronic

- Cc bnh l khc

Khng c thng s DH no cho php nh gi chnh xc tnh trng v

mc tn thng gan.

- Trnh k n cc thuc b kh hot mnh qua hiu ng vt qua

ln u hay cc thuc c t l gn kt protein cao

- Gim liu cc thuc b chuyn ho gan qua cytochrome P450

Cc yu t khc

- Ru

- Thuc l

- Thc n

duoc dong hoc - ths. nguyen thi mai hoang

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