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

Pregabalin a
≥90 b 90-99 0 0.96-1.2 c 0.5 5-6.5 1 b 8.5 μg/mL e
b RD d
a
Pregabalin undergoes minimal metabolism; an N-methylated metabolite has been identified
in urine and accounts for 0.9% of oral dose. >90% of dose is excreted in urine as unchanged
drug. Pregabalin pharmacokinetics is dose independent and predictable from single to multiple
dosing. b Bioavailability does not vary with dose up to 600 mg. T max
is delayed from 1 hour
to 3 hours and C max
decreased by 25-30% when pregabalin is given with food. No change in
AUC or extent of absorption is noted. c Mean renal clearance in healthy young subjects ranges
from 67 to 81 mL/min and assuming 70-kg body weight. d Pregabalin clearance is proportional
CL cr
; hence, dosage can be adjusted in accordance to CL cr
in renal dysfunction. Plasma
Procainamide a
83 ± 16 67 ± 8 16 ± 5 CL = 2.7CL cr
+ 1.7 1.9 ± 0.3 3.0 ± 0.6 M: 3.6 d M: 2.2 μg/mL d
b CHF, COPD, + 3.2 (fast) b or + b Obes a RD c F: 3.8 d F: 2.9 μg/mL d
CP, LD 1.1 (slow) b i RD, Child, MI
a Child Tach, CHF b Child, Neo
b MI
i Obes, Tach,
i CHF, Tach, Neo
CHF
a
Active metabolite, N-acetylprocainamide (NAPA); CL = 3.1 ± 0.4 mL/min/kg, V =
1.4 ± 0.2 L/kg, and t 1/2
= 6.0 ± 0.2 hours. b CL calculated using units of mL/min/kg for CL cr
.
CL depends on NAT2 acetylation phenotype. Use a mean value of 2.2 if phenotype unknown.
c
t 1/2
for procainamide and NAPA increased in patients with RD. d Least square mean values
following 1000-mg oral dose given twice daily to steady state in male (M) and female (F)
adults. Mean peak NAPA concentrations were 2.0 and 2.2 μg/mL for male and female adults,
respectively; T max
= 4.1 and 4.2 hours, respectively.
Promethazine a
pregabalin decreased by ~50% after 4 hours of hemodialysis. e Steady-state concentration in
healthy subjects receiving 200-mg pregabalin every 8 hours.
References: Bialer M, et al. Progress report on new antiepileptic drugs: A summary of the fifth
Eilat conference (EILAT V). Epilepsy Res, 2001, 43:11–58. Brodie MJ, et al. Pregabalin drug
interaction studies: Lack of effect on the pharmacokinetics of carbamazepine, phenytoin, lamotrigine,
and valproate in patients with partial epilepsy. Epilepsia, 2005, 46:1407–1413. Physicians’
Desk Reference, 63rd ed. Montvale, NJ, Physicians’ Desk Reference Inc., 2008, pp. 2527–2534.
References: Benet LZ, et al. Die renale Elimination von Procainamide: Pharmacokinetik bei
Niereninsuffizienz. In: Braun J, et al., eds. Die Behandlung von Herzrhythmusstorungen bei
Nierenkranken. Basel, Karger, 1984, pp. 96–111. Koup JR, et al. Effect of age, gender, and
race on steady state procainamide pharmacokinetics after administration of Procanbid sustained-release
tablets. Ther Drug Monit, 1998, 20:73–77.
PO: 27.9 ± 19.8 b 0.64 ± 0.49 93 15.7 ± 5.7 13.4 ± 3.6 d 12.2 ± 2.2 PO: 2.8 ± 1.4 e PO: 21.8 ± 14.0
ng/mL e
Rectal: 21.7-23.4 c Rectal: Rectal:
8.2 ± 3.4 11.3 ± 8.5 ng/mL
a
Promethazine undergoes ring-hydroxylation mediated by CYP2D6, N-demethylation by
CYP2B6, and S-oxidation to a sulfoxide. Promethazine is well absorbed following oral
administration (>80%) but is subject to first-pass metabolism, which explains its low systemic
availability. b Oral bioavailability at 75-mg dose as compared to IV bolus. c Bioavailability of
two commercial rectal suppositories at a 50-mg dose compared to an IM dose. d Steady-state
volume. e Data for a 50-mg oral dose of promethazine in solution. f Following a 50-mg dose of
promethazine rectal suppository.
References: Drugs@FDA. AcipHex label approved on 6/30/08. Available at:
http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/Accessed on August 2, 2009.
Koytchev R, et al. Absolute bioavailability of chlorpromazine, promazine and promethazine.
Arzneimittelforschung, 1994, 44:121–125. Schwinghammer TL, et al. Comparison of the
bioavailability of oral, rectal and intramuscular promethazine. Biopharm Drug Dispos, 1984,
5:185–194. Sharma A, et al. Classic histamine H1 receptor antagonists: A critical review of
their metabolic and pharmacokinetic fate from a bird’s eye view. Curr Drug Metab, 2003,
4:105–129. Stavchansky S, et al. Bioequivalence and pharmacokinetic profile of promethazine
hydrochloride suppositories in humans. J Pharm Sci, 1987, 76:441–445. Taylor G, et al.
Pharmacokinetics of promethazine and its sulphoxide metabolite after intravenous and oral
administration to man. Br J Clin Pharmacol, 1983, 15:287–293.
(Continued)
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
1967