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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
QU TRNH CHUYN HO (BIN I SINH HC)
QU TRNH CHUYN HO (BIN I SINH HC)
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
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
Vd: isoniazidAcetyl ho chm
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.
TNG TC THUC
Cc cht gy c ch men: cimetidine, chloramphenicol, isoniazid,
dicoumarol, ketoconazole, disulfiram, allopurinol,
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.
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)
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)
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
T1/2 = 0.693
k(5)
GIAI ON THI TR (BI TIT)
Cc thng s dc ng c bn ca s thi tr
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.
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
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)
GIAI ON THI TR (BI TIT)
Mi lin h gia cc thng s dc ng hc
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
GIAI ON THI TR (BI TIT)
Mi lin h gia cc thng s dc ng hc
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)
GIAI ON THI TR (BI TIT)
Mi lin h gia cc thng s dc ng hc
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)
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
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