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

Rabebrazole a
52 b 0 b 95-98 4.2 ± 1.2 c 0.37 c 1.0 ± 0.6 c 3.8-4.6 EM: 437 ± 241 ng/mL d
a
Rabeprazole is primarily converted non-enzymatically to rabeprazole-thioether; some of it is
oxidized to desmethylrabeprazole and rabeprazole sulfone by CYP2C19 and CYP3A4,
respectively. CYP2C19 genetic polymorphism has a modest effect on rabeprazole clearance.
Rabeprazole possesses an asymmetric sulfur center; the enantiomers inhibit H + /K + -ATPase
with equal potency in vitro. b ~90% of radiolabeled oral dose is recovered in urine, indicating
near-complete gastrointestinal absorption. Incomplete systemic availability is due to instability
and first-pass metabolism of rabeprazole. c Based on data from a 20-mg IV dose of
rabeprazole in subjects with unknown CYP2C19 genotype or phenotype, most likely reflecting
characteristics of extensive metabolizers (EM). Elimination t 1/2
up to 2-3 hours has been
observed in poor metabolizers (PM) of CYP2C19 following oral rabeprazole. d At steady state
during a 20-mg once-a-day regimen for duodenal ulcer.
Raloxifene a
PM: 600 ± 319 ng/mL d
2 b <0.2 >95 735 ± 338 c 2348 ± 1220 c 28 (11-273) 6 d 0.5 ± 0.3 ng/mL d
i RD, Aged
b LD
a
Data from postmenopausal women. Undergoes extensive first-pass metabolism (UGT catalyzed)
and enterohepatic recycling. b ~60% absorption from the gastrointestinal tract; not significantly
affected by food. c CL/F and V/F reported for an oral dose. d Following a single
1-mg/kg oral dose.
Raltegravir a
References: Yasuda S, et al. Comparison of the kinetic disposition and metabolism of E3810,
a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4′-hydroxylation
status. Clin Pharmacol Ther, 1995, 58:143–154. Yasuda S, et al. Pharmacokinetic properties
of E3810, a new proton pump inhibitor, in healthy male volunteers. Int J Clin Pharmacol
Ther, 1994, 32:466–473. Setoyama T, et al. Mass balance study of [ 14 C] rabeprazole following
oral administration in healthy subjects. Int J Clin Pharmacol Ther, 2006, 44:557–565.
Setoyama T, et al. Pharmacokinetics of rabeprazole following single intravenous and oral
administration to healthy subjects. Int J Clin Pharmacol Ther, 2005, 43:37–42.
References: Hochner-Celnikier D. Pharmacokinetics of raloxifene and its clinical application.
Eur J Obstet Gynecol Reprod Biol, 1999, 85:23–29. PDR54, 2000, p. 1583.
≥31.8 ± 9.4 b 8.8 ± 4.7 83 16.1 (11.4, 22.6) c α: 0.92 ± 0.21 d 1.0 e 4.5 (2.0, 10.2) μM e
i RD
β: 12.5 ± 4.6 d
a Hemodialysis
i LD (modest)
a
Raltegravir undergoes O-glucuronidation mediated largely by UGT1A1 and to a lesser extent
by UGT1A3 and UGT1A9. Raltegravir AUC is only modestly elevated in individuals with
UGT1A1*28/*28 genotype compared to *1/*1 genotype. b The absolute oral bioavailability of
raltegravir has not been determined. This minimum extent of oral absorption is based upon
recovery of radioactivity in urine following oral administration of 14 C-labeled raltegravir in
healthy human subjects. c Geometric mean (95% confidence interval) of pharmacokinetic
parameters following a single 400-mg oral dose. Apparent oral clearance (CL/F) is listed.
d
Plasma concentration time course of raltegravir exhibits multiphasic washout kinetics. Initial
(α) and terminal (β) t 1/2
s are reported because the early phase accounts for a large portion of
the AUC from time 0 to ∞. e Median for T max
and geometric mean (95% confidence interval)
for C max
following a 400-mg twice-daily monotherapy regimen for 10 days in treatment-naive
patients with HIV-1 infection.
References: Drugs@FDA. Isentress label approved on 7/8/09. Available at:
http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/. Accessed on August 22, 2009.
Kassahun K, et al. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-
AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab
Dispos, 2007, 35:1657–1663. Wenning LA, et al. Lack of a significant drug interaction
between raltegravir and tenofovir. Antimicrob Agents Chemother, 2008, 52:3253–3258.
Wenning LA, et al. Pharmacokinetics of raltegravir in individuals with UGT1A1 polymorphisms.
Clin Pharmacol Ther, 2009, 85:623–627.
(Continued)
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
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