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

Mercaptopurine a
12 ± 7 b 22 ± 12 19 11 ± 4 c 0.56 ± 0.38 0.90 ± 0.37 IV: 6.9 μM d
a
Inactive prodrug is metabolized intracellularly to 6-thioinosinate. Pharmacokinetic values for
mercaptopurine are reported. b Increases to 60% when first-pass metabolism is inhibited by
allopurinol (100 mg three times daily). c Metabolically cleared by xanthine oxidase and thiopurine
methyltransferase (polymorphic). Despite inhibition of intrinsic CL by allopurinol, hepatic
metabolism is limited by blood flow, and CL is thus little changed by allopurinol. d Following
Metformin a
PO (−): 2.4 ± PO (−): 0.74 ±
0.4 d 0.28 μM d
PO (+): 2.8 ± PO (+): 3.7 ±
0.4 d 0.6 μM d
52 ± 5 99.9 ± 0.5 Negligible 7.62 ± 0.30 1.12 ± 0.08 1.74 ± 0.20 1.9 ± 0.4 c 1.6 ± 0.2 μg/mL c
(40-55) (79-100) (6.3-10.1) (0.9-3.94) (1.5-4.5) (1.5-3.5) c (1.0-3.1 μg/mL) c
b RD, b Aged
a RD, b Aged
a
Data from healthy male and female subjects. No significant gender differences. Shown in
parentheses are mean values from different studies. b CL/F reduced, mild to severe renal
impairment. c Following a single 0.5-g oral dose (tablet) and range for a 0.5- to 1.5-g oral
dose.
Methadone a
an IV infusion of 50 mg/m 2 /hr to steady state in children with refractory cancers or a single
oral dose of 75 mg/m 2 with (+) or without (−) allopurinol pretreatment.
References: Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin
Pharmacol, 1992, 43:329–339. PDR54, 2000, p. 1255.
92 ± 21 24 ± 10 b 89 ± 2.9 c 1.7 ± 0.9 b 3.6 ± 1.2 d 27 ± 12 e ~3 f IV: 450-550 ng/mL f
b Burn, Child b Burn, Child PO: 69-980 ng/mL f
a
Data for racemic mixture. Opioid activity resides with the R-enantiomer. In vivo disposition is
stereoselective. N-demethylation is mediated by CYP3A4 and CYP2B6. b Inversely correlated
with urine pH. c d-methadone slightly higher percent bound. d V area
reported. Directly correlated
with urine pH. e Directly correlated with urine pH. f Following a single 10-mg IV bolus dose in
patients with chronic pain or a 0.12- to 1.9-mg/kg oral dose once daily for at least
2 months in subjects with opioid dependency. Levels >100 ng/mL prevent withdrawal symptoms;
EC 50
for pain relief and sedation in cancer patients is 350 ± 180 ng/mL.
References: Harrower AD. Pharmacokinetics of oral antihyperglycaemic agents in patients
with renal insufficiency. Clin Pharmacokinet, 1996, 37:111–119. Pentikainen PJ, et al.
Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin
Pharmacol, 1979, 16:195–202. PDR54, 2000, pp. 831–835. Scheen AJ. Clinical pharmacokinetics
of metformin. Clin Pharmacokinet, 1996, 30:359–371.
References: Dyer KR, et al. Steady-state pharmacokinetics and pharmacodynamics in
methadone maintenance patients: Comparison of those who do and do not experience withdrawal
and concentration-effect relationships. Clin Pharmacol Ther, 1999, 65:685–694.
Inturrisi CE, et al. Pharmacokinetics and pharmacodynamics of methadone in patients with
chronic pain. Clin Pharmacol Ther, 1987, 41:392–401.
(Continued)
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
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