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
Methotrexate a
70 ± 27 b,c 81 ± 9 46 ± 11 2.1 ± 0.8 0.55 ± 0.19 7.2 ± 2.1 d SC: 0.9 ± 0.2 e SC: 1.1 ± 0.2 μM e
b RD i RA IV: 37-99 μM e
i RA
a
Plasma concentrations of the 7-hydroxy metabolite approach those of the parent drug.
Metabolite may have both therapeutic and toxic effects. b Bioavailability is dose dependent and
may be as low as 20% when doses are >80 mg/m 2 . c IM bioavailability is only slightly higher.
d
Exhibits triexponential elimination kinetics. A shorter t 1/2
(2 hours) is seen initially, and a
longer (52 hours) terminal t 1/2
has been observed with increased assay sensitivity. e Following a
15-mg SC dose given once weekly to steady state in adult patients with inflammatory bowel
disease. Initial steady-state concentrations in young (1.5-22 years of age) leukemia patients
receiving a 500-mg/m 2 loading dose given over 1 hour followed by an infusion of 196
mg/m 2 /hr for 5 hours.
Methylphenidate a
References: Egan LJ, et al. Systemic and intestinal pharmacokinetics of methotrexate in
patients with inflammatory bowel disease. Clin Pharmacol Ther, 1999, 65:29–39. Tracy TS,
et al. Methotrexate disposition following concomitant administration of ketoprofen, piroxicam
and flurbiprofen in patients with rheumatoid arthritis. Br J Clin Pharmacol, 1994,
37:453–456. Wall AM, et al. Individualized methotrexate dosing in children with relapsed
acute lymphoblastic leukemia. Leukemia, 2000, 14:221–225.
(+): 22 ± 8 (+): 1.3 ± 0.5 (+/−): 15-16 (+): 6.7 ± 2.0 b (+): 2.7 ± 1.1 (+): 6.0 ± 1.7 c (+): 2.4 ± 0.8 c,d (+): 18 ± 4.3 ng/mL d
(−): 5 ± 3 (−): 0.6 ± 0.3 (−): 12 ± 4.7 b (−): 1.8 ± 0.9 (−): 3.6 ± 1.1 (−): 2.1 ± 0.6 d (−): 3.0 ± 0.9 ng/mL d
a
Methylphenidate is available as a racemate and the active (+)-dextro-enantiomer,
dexmethylphenidate. Methylphenidate and dexmethylphenidate are extensively metabolized,
primarily through ester hydrolysis to ritalinic acid. Data for individual enantiomers following
racemate administration to healthy adult male subjects. No significant gender differences. b The
(+)-enantiomer exhibits dose-dependent kinetics at high doses of racemate, with a ~50% reduction
in CL/F between a 10- to 40-mg dose. c When dexmethylphenidate is given alone, its t 1/2
is
2.2 hours, and T max
is 1-1.5 hours. d Following a single 40-mg oral dose (immediate release).
Longer T max
(3-5 hours) and lower C max
reported for sustained-released oral formulation.
References: Aoyama T, et al. Nonlinear kinetics of threo-methylphenidate enantiomers in a
patient with narcolepsy and in healthy volunteers. Eur J Clin Pharmacol, 1993, 44:79–84.
Keating GM, et al. Dexmethylphenidate. Drugs, 2002, 62:1899–1904; discussion 1905–1908.
Kimko HC, et al. Pharmacokinetics and clinical effectiveness of methylphenidate. Clin
Pharmacokinet, 1999, 37:457–470. PDR58, 2004, pp. 2265, 2297–2298. Srinivas NR, et al.
Enantioselective pharmacokinetics of dl-threo-methyl-phenidate in humans. Pharm Res,
1993, 10:14–21.