DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Clopidogrel a
— b — Clo: 98 — — Clo: 4-6 Clo: 0.5-1 Clo d
a
Clopidogrel (Clo) is a prodrug that is converted to a minor unstable active metabolite (AM)
via two sequential cytochrome P450-dependent reactions. The majority of the dose gets
converted rapidly to an inactive hydrolytic product by esterases. Although multiple P450
isoforms contribute to the formation of AM, blood levels of AM have been associated with the
CYP2C19 genotype and phenotype status, with poor metabolizers (PM) exhibiting lower
levels, on average, than extensive metabolizers (EM). Formation of AM accounts for ≤10% of
the administered dose and may be dose dependent due to saturable metabolism. b The absolute
bioavailability of Clo is unknown. There is one report of food greatly enhancing the systemic
exposure of Clo following oral administration. c The reported value may represent disappearance
of high levels of metabolite formed during first-pass and not the terminal t 1/2
, which
should be formation limited. d Following a single 300-mg loading dose of Clo.
Clorazepate a
AM: 0.5 c AM: 1.0 d EM: 3.8 ± 2.5 ng/mL
IM: 6.8 ± 3.6 ng/mL
PM: 18 ± 14 ng/mL
AM d
EM: 39 ± 15 ng/mL
IM: 26 ± 11 ng/mL
PM: 24 ± 6 ng/mL
N: 91 ± 6 a N: <1 N: 97.5 N: 0.17 ± 0.02 c N: 1.24 ± 0.09 c N: 93 ± 11 c N: 0.72 ± N: 275 ± 27 ng/mL a,d
b RD a Smk a Obes, Preg a Obes, Preg, 0.01 a,d
i Obes, b Hep, LD, i Hep, LD, Aged b
Aged b Obes, Aged b Aged b Hep, LD, Smk
a
Clorazepate is essentially a prodrug for nordiazepam (N). Bioavailability, T max
, and C max
values
for N were derived after oral administration of clorazepate. b Significantly different for
male subjects only. c CL, V ss
, and t 1/2
values are for IV nordiazepam. d Data for N following a
20-mg IM dose of clorazepate given to nonpregnant women.
Clozapine
References: Farid NA, et al. Metabolism and disposition of the thienopyridine antiplatelet
drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol, 2009, Nov 30
[Epub ahead of print]. Kim KA, et al. The effect of CYP2C19 polymorphism on the pharmacokinetics
and pharmacodynamics of clopidogrel: A possible mechanism for clopidogrel
resistance. Clin Pharmacol Ther, 2008, 84:236–242. Takahashi M, et al. Quantitative determination
of clopidogrel active metabolite in human plasma by LC-MS/MS. J Pharm Biomed
Anal, 2008, 48:1219–1224. Umemura K, et al. The common gene variants of CYP2C19 affect
pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy
subjects. J Thromb Haemost, 2008, 6:1439–1441.
References: Greenblatt DJ, et al. Desmethyldiazepam pharmacokinetics: Studies following
intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam. J Clin
Pharmacol, 1988, 28:853–859. Rey E, et al. Pharmacokinetics of clorazepate in pregnant and
non-pregnant women. Eur J Clin Pharmacol, 1979, 75:175–180.
55 ± 12 <1 >95 6.1 ± 1.6 5.4 ± 3.5 12 ± 4 1.9 ± 0.8 a 546 ± 307 ng/mL a
a
Following titration up to a 150-mg oral dose (tablet) given twice daily for 7 days to adult
chronic schizophrenics.
References: Choc MG, et al. Multiple-dose pharmacokinetics of clozapine in patients. Pharm
Res, 1987, 4:402–405. Jann MW, et al. Clinical pharmacokinetics of the depot antipsychotics.
Clin Pharmacokinet, 1985, 10:315–333.
(Continued)
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
1917