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
Isosorbide 5-Mononitrate (Isosorbide Nitrate) a
93 ± 13 <5 0 1.80 ± 0.24 0.73 ± 0.09 4.9 ± 0.8 1-1.5 b 314-2093 nM b
i LD, RD, i LD, RD, i LD, RD, i LD, RD, MI,
Aged, CAD Aged, CAD MI, Aged, Aged, CAD
CAD
a
Active metabolite of isosorbide dinitrate. b Following a 20-mg oral dose given by asymmetric
dosing (0 and 7 hours) for 4 days.
Isotretinoin a
40 b Negligible >99 5.5 (0.9-11.1) c 5 (1-32) c 17 (5-167) d I: 4.5 ± 3.4 e I: 208 ± 92 ng/mL e
a Food 4-oxo: 6.8 ± 6.5 e 4-oxo: 473 ±
171 ng/mL e
a
Isotretinoin (I) is eliminated through metabolic oxidations catalyzed by multiple CYPs (2C8,
2C9, 3A4, and 2B6). The 4-oxo-isotretinoin metabolite (4-oxo) is active and found at higher
concentrations than parent drug at steady state. b Bioavailability when taken with food is
reported. c CL/F and V/F reported. d 4-oxo has an apparent mean t 1/2
of 29 ± 6 hours. e Values
for I and 4-oxo following a 30-mg oral dose given once daily to steady state.
Itraconazole a
Reference: Abshagen UW. Pharmacokinetics of isosorbide mononitrate. Am J Cardiol, 1992,
70:61G–66G.
References: Larsen FG, et al. Pharmacokinetics and therapeutic efficacy of retinoids in skin
diseases. Clin Pharmacokinet, 1992, 23:42–61. Nulman I, et al. Steady-state pharmacokinetics
of isotretinoin and its 4-oxo metabolite: Implications for fetal safety. J Clin Pharmacol,
1998, 38:926–930. Wiegand UW, et al. Pharmacokinetics of oral isotretinoin. J Am Acad
Dermatol, 1998, 39:S8–S12.
55 <1 99.8 5.1 c 10.7 d 21 ± 6 e 3-5 f 649 ± 289 ng/mL f
a Food
a Food
b HIV b
a
Metabolized predominantly by CYP3A4 to an active metabolite, hydroxyitraconazole, and
other sequential metabolites. b Relative to oral dosing with food. c Blood CL is 9.4 mL/min/kg.
CL is concentration dependent; the value given is nonsaturable range. K m
= 330 ± 200 ng/mL,
V max
= 2.2 ± 0.8 pg · mL −1 · min −1 · kg −1 . Apparent CL/F at steady state reported to be 5.4 mL ·
min −1 · kg −1· d V area
reported. Follows multicompartment kinetics. Does not appear to be concentration
dependent. e t 1/2
for the nonsaturable concentration range. t 1/2
at steady state reported
to be 64 hours. f Following a 200-mg oral dose given daily for 4 days to adults.
References: Heykants J, et al. The pharmacokinetics of itraconazole in animals and man. An
overview. In: Fromtling RA, ed. Recent Trends in the Discovery, Development and Evaluation
of Antifungal Agents. Barcelona, Prous Science Publisher, 1987, pp. 223–249. Jalava KM, et
al. Itraconazole greatly increases plasma concentrations and effects of felodipine. Clin
Pharmacol Ther, 1997, 61:410–415.