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. 2014 May;47(3):89-96.
doi: 10.1055/s-0034-1371866. Epub 2014 Apr 24.

Can valproic acid be an inducer of clozapine metabolism?

F J Diaz  1 , C B Eap  2 , N Ansermot  2 , S Crettol  2 , E Spina  3 , J de Leon  4
Affiliations

Can valproic acid be an inducer of clozapine metabolism?

F J Diaz et al. Pharmacopsychiatry. 2014 May.

Abstract

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.

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Conflict of interest statement

Conflict of interest

No commercial organizations had any role in the writing of this paper for publication. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. For his participation in the study reported in this article, or in the writing of this article, Dr. Diaz did not receive any salary or payment from the other authors or from grants awarded to them. In the past three years, Dr. Diaz had no conflict of interest.

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