Can Valproic Acid be an Inducer of Clozapine Metabolism?

被引:41
作者
Diaz, F. J. [1 ]
Eap, C. B. [2 ,3 ]
Ansermot, N. [2 ]
Crettol, S. [2 ]
Spina, E. [4 ]
de Leon, J. [5 ,6 ]
机构
[1] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS 66103 USA
[2] Univ Lausanne, Hosp Cery, Dept Psychiat, Unit Pharmacogenet & Clin Psychopharmacol,Ctr Psy, Prilly, Switzerland
[3] Univ Lausanne, Univ Geneva, Sch Pharmaceut Sci, Geneva, Switzerland
[4] Univ Messina, Dept Clin & Expt Med, Messina, Italy
[5] Eastern State Hosp, Mental Hlth Res Ctr, Lexington, KY 40511 USA
[6] Univ Granada, Inst Neurosci, Psychiat & Neurosci Res Grp CTS 549, Granada, Spain
关键词
clozapine; pharmacokinetics; metabolism; enzyme induction; drug interactions; therapeutic drug monitoring; valproic acid; smoking; tobacco; random-effects linear model; SERUM CONCENTRATIONS; DRUG-INTERACTIONS; CYP1A2; ACTIVITY; CO-MEDICATIONS; PLASMA; OLANZAPINE; DOSAGE; PHARMACOKINETICS; POLYMORPHISMS; POPULATION;
D O I
10.1055/s-0034-1371866
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Introduction: Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that (i) VPA is a net inducer of clozapine metabolism, and (ii) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. Methods: After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. Results: VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14-39%) after controlling for confounding variables including smoking (35% lower, 28-56%). Discussion: Prospective studies are needed to definitively establish that VPA may (i) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and (ii) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism.
引用
收藏
页码:89 / 96
页数:8
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