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

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APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
Table AII–1
Pharmacokinetic Data (Continued)
BIOAVAILABILITY URINARY BOUND IN CLEARANCE VOL. DIST. HALF-LIFE PEAK TIME PEAK
(ORAL) (%) EXCRETION (%) PLASMA (%) (mL/min/kg) (L/kg) (hours) (hours) CONCENTRATION
Rosuvastatin a
20 (17-23) 30 ± 7 88 10.5 ± 4.7 1.7 ± 0.5 20 ± 6 3 (l-6) c 4.6 ± 2.1 ng/mL c
b RD b
a
Eliminated primarily by biliary excretion; also appears to be actively transported into the
liver by an organic anion transport protein (OATP2/SLC21A6). Data from healthy men
reported; no significant gender or age differences. b Reduced CL/F in patients with severe
renal impairment. c Following a 10-mg oral dose taken once daily for 10 days.
References: Martin PD, et al. Absolute oral bioavailability of rosuvastatin in healthy white
adult male volunteers. Clin Ther, 2003, 25:2553–2563. Martin PD, et al. Pharmacodynamic
Selegiline a
Negligible b Negligible 94 c ~1500 b 1.9 1.91 ± 1.0 e S: 0.7 ± 0.4 f S: 1.1 ± 0.4 ng/mL f
160 d DS: ~1 hr DS: ~15 ng/mL f
a
MAO-B active metabolite: l-(–)-desmethylselegiline. b Extensive first-pass metabolism; estimate
of CL/F reported. c Blood-to-plasma concentration ratio = 1.3-2.2 for parent drug and
~0.55 for N-desmethyl metabolite. d CL/F for N-desmethylselegiline, assuming quantitative
conversion of parent to this metabolite. e For parent and N-desmethyl metabolite. t 1/2
s for
methamphetamine (major plasma species) and amphetamine are 21 and 18 hours,
Sertraline
— a <1 98-99 38 ± 14 b — 23 M: 6.9 ± 1.0 c M: 118 ± 22 ng/mL c
b Aged, LD a Aged, LD F: 6.7 ± 1.8 c F: 166 ± 65 ng/mL c
a
Absolute bioavailability is not known (>44% absorbed); undergoes extensive first-pass
metabolism to essentially inactive metabolites; catalyzed by multiple CYP isoforms. b CL/F
reported. c Following a dose titration up to 200 mg given once daily for 30 days to healthy
male (M) and female (F) adults.
Sildenafil a
effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after
morning or evening administration in healthy volunteers. Br J Clin Pharmacol, 2002,
54:472–477. Product labeling: Crestor ® tablets (rosuvastatin calcium). Wilmington, DE,
Astra-Zeneca Pharmaceuticals LP, 2003. Schneck DW, et al. The effect of gemfibrozil on the
pharmacokinetics of rosuvastatin. Clin Pharmacol Ther, 2004, 75:455–463.
respectively. f Mean data for selegiline (S) and its active metabolite, N-desmethylselegiline
(DS), following a single 10-mg oral dose given to adults.
Reference: Heinonen EH, et al. Pharmacokinetic aspects of l-deprenyl (selegiline) and its
metabolites. Clin Pharmacol Ther, 1994, 56:742–749.
i Aged
References: van Harten J. Clinical pharmacokinetics of selective serotonin reuptake inhibitors.
Clin Pharmacokinet, 1993, 24:203–220. Warrington SJ. Clinical implications of the pharmacology
of sertraline. Int Clin Psychopharmacol, 1994, 6(suppl 2):11–21.
38 0 96 6.0 ± 1.1 1.2 ± 0.3 2.4 ± 1.0 1.2 ± 0.3 d 212 ± 59 ng/mL d
b LD, b RD, c Aged
a Aged d
a
Data from healthy male subjects. Sildenafil is metabolized primarily by CYP3A and secondarily
by CYP2C9. Piperazine N-desmethyl metabolite is active (~50% parent) and accumulates
in plasma (~40% parent). b CL/F reduced, mild to moderate hepatic impairment. c CL/F
reduced, severe renal impairment. Increased unbound concentrations. d Following a single
50-mg oral (solution) dose.
References: PDR54, 2000, p. 2382. Walker DK, et al. Pharmacokinetics and metabolism of
sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica, 1999, 29:297–310.