I CNG V DC NG HC

TS. ng Nguyn oan Trang 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.

Dc lc hc (Pharmacodynamics, PD)

Dc ng hc (Pharmacokinetics, PK)

Thuc

C th

nh ngha dc ng hc 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 thuc y (Thrapie,1978).

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

Hp thu (Absorption) Phn b (Distribution) Chuyn ho (Metabolism) Thi tr (Excretion)

Dc ng hc (Pharmacokinetics)

S ADME
Thuc dng ng ung Thuc dng ng IV

Thi tr

Drug Absorption

Hp thu

Thuc trong mu
Chuyn ho

Sn phm thi tr Sn phm chuyn ho

Phn b

Thuc dng ng 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) AUC ng ung (PO) F= AUC ng tnh mch (IV) x Liu PO Liu IV (1)

SKD tng i (so vi dng bo ch mu chn la, cng liu v cng ng cho thuc) AUC dng th nghim (PO) F= AUC dng mu (PO) (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%: kh t yu cu cho tc dng ton thn, cho tc ng ti ng tiu ho nu dng ng ung. SKD tuyt i > 50%: cho tc dng ton thn SKD tuyt i > 80%: lng thuc vo mu xp x ng tnh mch

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

A B C

MTC

MEC

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.

S ADME
Thuc dng ng ung Thuc dng ng IV

Thi tr

Drug Absorption

Hp thu

Thuc trong mu
Chuyn ho

Sn phm thi tr Sn phm chuyn ho

Phn b

Thuc dng ng SC, IM

GIAI ON PHN B
S phn b mu

Albumin (50-60% protein huyt tng), globulin, alpha-1-glycoprotein acid, lipoprotein

Thuc-Protein Hot cht Mu Thuc dng t do Phn tn vo m Cho tc ng Lc qua cu thn

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 c i lc vi huyt tng Thuc-protein huyt tng << Thuc-protein m Thuc c i lc vi m

GIAI ON PHN B
S phn b m Cc yu t nh hng n s phn b thuc m: - c tnh l ho ca thuc Vd: Cc thuc gy m thng c ch s lipid/nc cao nn thm vo c cc t bo thn kinh. Lng thuc gy m cn a cho ngi bo ph thng cao hn ngi bnh thng c cng cn nng

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
D: Dose (Liu) (g/mg) DxF Vd = Cp (3a) F: Sinh kh dng (%) Cp: Nng thuc trong huyt tng (g/L, mg/mL) Vd x Cp Loading dose = 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
3

Cht chuyn ho V hot

2 1

C hot tnh

V hot (tin cht)

C hot tnh (c tnh)

QU TRNH CHUYN HO (BIN I SINH HC)

QU TRNH CHUYN HO (BIN I SINH HC)

Giai on I Kiu phn ng Loi tc ng ca phn ng Oxy ho, kh, thu phn Bin i hay hnh thnh 1 nhm chc ho hc

Giai on II Lin hp Gn thm mt thnh phn thng l c cc

Cc men tc ng trong phn ng

Monooxygenase ph thuc Cytochrome P450 (CYP 450)

Transferase

QU TRNH CHUYN HO (BIN I SINH HC)

QU TRNH CHUYN HO (BIN I SINH HC)

Cc enzyme chnh trong h thng cytochrome P450 tham gia chuyn ho thuc

QU TRNH CHUYN HO (BIN I SINH HC)

Cc yu t nh hng n s chuyn ho thuc gan - Yu t di truyn Acetyl ho chm Vd: isoniazid Acetyl ho nhanh - Yu t tui tc Vd: tch t nordiazepam do thiu men chuyn ho tr s sinh

QU TRNH CHUYN HO (BIN I SINH HC)

Cc yu t nh hng n s chuyn ho thuc gan - 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

QU TRNH CHUYN HO (BIN I SINH HC)

Cc yu t nh hng n s chuyn ho thuc gan 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.

QU TRNH CHUYN HO (BIN I SINH HC)

Cc yu t nh hng n s chuyn ho thuc gan - 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. Cc cht gy c ch men: cimetidine, chloramphenicol, isoniazid, dicoumarol, ketoconazole, disulfiram, allopurinol, TNG TC THUC

QU TRNH CHUYN HO (BIN I SINH HC)

Cc yu t nh hng n s chuyn ho thuc gan 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.

GIAI ON THI TR (BI TIT)

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 (4) ClT : thanh lc ton phn ClR : thanh lc thn ClER: thanh lc ngoi thn

GIAI ON THI TR (BI TIT)

Cc thng s dc ng c bn ca s thi tr
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.

GIAI ON THI TR (BI TIT)

Cc thng s dc ng c bn ca s thi tr
Thi gian bn thi (Half-life ) (T1/2): l thi gian cn thit nng thuc trong huyt tng gim i mt na.

GIAI ON THI TR (BI TIT)

Cc thng s dc ng c bn ca s thi tr

k hay ke : hng s tc thi tr

GIAI ON THI TR (BI TIT)

Cc thng s dc ng c bn ca s 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 0.693 k

T1/2 =

(5)

GIAI ON THI TR (BI TIT)

Cc thng s dc ng c bn ca s thi tr
S ln T1/2 1 2 3 4 5 6 7 Lng thuc c thi tr (%) 50 75 88 94 97 98 99

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

GIAI ON THI TR (BI TIT)

Trng thi n nh (steady state)

GIAI ON THI TR (BI TIT)

Trng thi n nh (steady state)

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

GIAI ON THI TR (BI TIT)

Mi lin h gia cc thng s dc ng hc Nu dng thuc bng ng tim tnh mch
D

ClT =

(6)

D: Dose (Liu)

AUC0- Nu dng thuc bng ng ung

DxF (7)

ClT =

AUC0-

GIAI ON THI TR (BI TIT)

Mi lin h gia cc thng s dc ng hc

Cl =

(8)

: Tc thanh lc (mg/pht)
e

Cp Cp: Nng thuc trong huyt tng (mg/pht)

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

Cl =

(9)

Css: Nng thuc trong huyt tng trng thi n nh (mg/pht)

Css

GIAI ON THI TR (BI TIT)

Mi lin h gia cc thng s dc ng hc Nu thuc c truyn ng tnh mch lin tc (IV infusion), trng thi n nh tc thi tr = tc truyn
Css =

inf)

e=

inf

/ Cl

hay inf = Cl x Css

(10)

Nu thuc c ung hay tim IV gin on, trng thi n nh (~5 T1/2):
Css = FxD Cl x t Css x Cl x t (11a) hay Maintenance dose = F (11b)

GIAI ON THI TR (BI TIT)

Mi lin h gia cc thng s dc ng hc Lin quan gia T1/2, Cl v Vd
0,693 x Vd T1/2 = Cl (12)

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

ln C0 Ct 0,693

x T1/2

(13)

GIAI ON THI TR (BI TIT)

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

Hp thu (Absorption) Phn b (Distribution) Chuyn ho (Metabolism) Thi tr (Excretion)

F Cmax Tmax AUC Vd

D
(Loading dose (liu tn cng), maintenance dose ( liu duy tr))

Dc ng hc (Pharmacokinetics)

Cp Css Cl T1/2 ke e (k)

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
Din tch ton c th (m2) x Liu ngi ln Liu tr em = 1,8 (140 tui) x Din tch ton c th (m2) Liu ngi cao tui = 153

x Liu ng l n

Cc yu t bnh l - Suy thn - Gim lc cu thn - Gim t l thuc gn vi protein huyt tng Liu (-) Liu Liu (-) S ln dng thuc S ln dng thuc S ln dng thuc

Cc yu t bnh l - Suy thn Cng thc Crockroft-Gault nh gi chc nng thn:

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

Khng c thng s DH no cho php nh gi chnh xc tnh trng v mc tn thng gan. - Nn chn nhng thuc o thi ch yu qua thn hoc lin hp glucuronic - 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 bnh l khc

Cc yu t khc - Ru - Thuc l - Thc n