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

Donepezil a
— b 10.6 ± 2.7 92.6 ± 0.9 c 2.90 ± 0.74 d 14.0 ± 2.42 d 59.7 ± 16.1 d 3-4 f 30.8 ± 4.2 ng/mL f
b LD, e a Aged a Aged
i RD
a
Data from young, healthy male, and female subjects. No significant gender differences.
Metabolized by CYP2D6, CYP3A4, and UGT. b Absolute bioavailability is unknown, but the
oral dose reportedly is well absorbed. c A fraction bound value of 96% also has been reported.
d
CL/F, V ss
/F, and t 1/2
reported for oral dose. e CL/F reduced slightly (~20%), alcoholic cirrhosis.
f Following a 5-mg oral dose given once daily to steady state.
Doxazosin a
Y: 65 ± 14 5 98 Y: 1.26 ± 0.27 Y: 1.0 ± 0.1 20.5 ± 6.1 c,d 3.9 ± 1.2 d 67 ± 19 ng/mL d
E: 68 ± 16 E: 2.25 ± 1.42 E: 1.7 ± 1.0 GITS: 19 ± 4 d GITS: 9 ± 5 d GITS: 28 ± 12
GITS: F rel
= b LD b i LD b ng/mL d
59 ± 12
a
Cleared primarily by cytochrome P450-dependent metabolism. Where indicated, data for
young (Y) and elderly (E) normotensive adults are reported. Also reported are data for a gastrointestinal
sustained-release device (GITS); oral bioavailability relative to standard formulation
(F rel
). b Study in patients with mild to moderate liver impairment; AUC increased 43%.
c
Shorter t 1/2
following IV dosing reported; (Y) 10 ± 1 hour, (E) 12 ± 5 hour; attributed to inadequate
duration of blood sampling. d Following an 8-mg dose of standard formulation or
GITS, once daily, to steady state in young and elderly normotensive volunteers.
Doxepin a
30 ± 10 b ~0 82 (75-89) 14 ± 3 c 24 ± 7 c,d 18 ± 5 D: 0.5-1 D: 28 ± 11 ng/mL e
a
The active metabolite, desmethyldoxepin, has a longer t 1/2
(37 ± 15 hours). b Calculated from
results of oral administration only, assuming complete absorption, elimination by the liver,
hepatic blood flow of 1.5 L/min, and equal partition between plasma and erythrocytes.
c
Calculated assuming F = 0.30. d V area
reported. e Trough concentrations of doxepin (D) and
References: Ohnishi A, et al. Comparison of the pharmacokinetics of E2020, a new compound
for Alzheimer’s disease, in healthy young and elderly subjects. J Clin Pharmacol, 1993,
33:1086–1091. PDR54, 2000, p. 2323.
References: Chung M, et al. Clinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal
therapeutic system (GITS) formulation. Br J Clin Pharmacol, 1999, 48:678–687.
Elliott HL, et al. Pharmacokinetic overview of doxazosin. Am J Cardiol, 1987, 59:78G–81G.
Penenberg D, et al. The effects of hepatic impairment on the pharmacokinetics of doxazosin.
J Clin Pharmacol, 2000, 40:67–73. Vincent J, et al. The pharmacokinetics of doxazosin in
elderly normotensives. Br J Clin Pharmacol, 1986, 21:521–524.
DD: 4-12
DD: 39 ± 19 ng/mL e
desmethyldoxepin (DD) following a 150-mg oral dose given once daily for 3 weeks to
patients with depression. Peak/trough ratio <2.
Reference: Faulkner RD, et al. Multiple-dose doxepin kinetics in depressed patients. Clin
Pharmacol Ther, 1983, 34:509–515.
(Continued)
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
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