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

Paroxetine
Dose dependent a <2 95 8.6 ± 3.2 a,b 17 ± 10 c 17 ± 3 d 5.2 ± 0.5 e EM: ~130 nM e
b LD, Aged a LD, Aged PM: ~220 nM e
a
Metabolized by CYP2D6 (polymorphic); undergoes time- and dose-dependent autoinhibition
of metabolic CL in extensive metabolizers (EM). b CL/F reported for multiple dosing in EM.
Single dose data are significantly higher. In CYP2D6 poor metabolizers (PM), CL/F = 5.0 ±
2.1 mL/min/kg for multiple dosing. c V area
/F reported. d Data reported for multiple dose in EM.
In PM, t 1/2
= 41 ± 8 hours. e Estimated mean C max
following a 30-mg oral dose given once
Phenobarbital
100 ± 11 24 ± 5 a 51 ± 3 0.062 ± 0.013 0.54 ± 0.03 99 ± 18 2-4 b 13.1 ± 4.5 μg/mL b
i LD, AVH b Neo a Preg, Child, Neo a Neo a LD, Aged
i Preg, Aged i Smk b Child
i Epilepsy, Neo
a
Phenobarbital is a weak acid (pK a
= 7.3); urinary excretion is increased at an alkaline pH;
it also is reduced with decreased urine flow. b Mean steady-state concentration following a
90-mg oral dose given daily for 12 weeks to patients with epilepsy. Levels of 10-25 μg/mL
provide control of tonic-clonic seizures, and levels of at least 15 μg/mL provide control of
febrile convulsions in children. Levels >40 μg/mL can cause toxicity; 65-117 μg/mL produce
Phenytoin a
daily for 14 days to adults phenotyped as CYP2D6 EM and PM. There is a significant disproportional
accumulation of drug in blood when going from single to multiple dosing due to
autoinactivation of CYP2D6.
References: PDR54, 2000, p. 3028. Sindrup SH, et al. The relationship between paroxetine
and the sparteine oxidation polymorphism. Clin Pharmacol Ther, 1992, 51:278–287.
stage III anesthesia—comatose but reflexes present; 100-134 μg/mL produce stage IV
anesthesia—no deep-tendon reflexes.
References: Bourgeois BFD. Phenobarbital and primidone. In: Wyllie E, ed. The Treatment
of Epilepsy: Principles and Practice, 2nd ed. Philadelphia, Williams & Wilkins, 1997, pp.
845–855. Browne TR, et al. Studies with stable isotopes II: Phenobarbital pharmacokinetics
during monotherapy. J Clin Pharmacol, 1985, 25:51–58.
90 ± 3 2 ± 8 89 ± 23 V max
= 5.9 ± 1.2 0.64 ± 0.04 d 6-24 e 3-12 f 0-5 μg/mL (27%) f
b RD, Hep, mg · kg –1 · day –1 a Neo, NS, a Prem c 5-10 μg/mL (30%) f
Alb, Neo, b Aged, RD b RD c 10-20 μg/mL (29%) f
AVH, LD, a Child i AVH, LTh, i AVH, LTh, 20-30 μg/mL (10%) f
NS, Preg, Burn K m
= 5.7 ± HTh HTh, Smk c >30 μg/mL (6%) f
i Obes, 2.9 mg/L b
Smk, Aged i Aged, b Child
a NS, RD c
b Prem c
i AVH, LTh,
HTh, Smk c
a
Metabolized predominantly by CYP2C9 (polymorphic) and also by CYP2C19 (polymorphic);
exhibits saturable kinetics with therapeutic doses. b Significantly decreased in the Japanese population.
c Comparison of CLs and t 1/2
s with similar doses in normal subjects and patients; nonlinear
kinetics not considered. d V area
reported. e Apparent t 1/2
is dependent on plasma concentration.
f
Population frequency of total phenytoin concentrations following a 300-mg oral dose (capsule)
given daily to steady state. Total levels >10 μg/mL associated with suppression of tonic-clonic
seizures. Nystagmus can occur at levels >20 μg/mL and ataxia at levels >30 μg/mL.
References: Eldon MA, et al. Pharmacokinetics and tolerance of fosphenytoin and phenytoin
administered intravenously to healthy subjects. Can J Neurol Sci, 1993, 20(suppl 4):S180.
Levine M, et al. Therapeutic drug monitoring of phenytoin. Rationale and current status. Clin
Pharmacokinet, 1990, 79:341–358. Tozer TN, et al. Phenytoin. In: Evans WE, et al., eds.
Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, 3rd ed. Vancouver,
WA, Applied Therapeutics, 1992, pp. 25-1–25-44.
APPENDIX II
DESIGN AND OPTIMIZATION OF DOSAGE REGIMENS: PHARMACOKINETIC DATA
(Continued)
1963