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Pharmacopsychiatry 2014; 47(03): 89-96
DOI: 10.1055/s-0034-1371866
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Can Valproic Acid be an Inducer of Clozapine Metabolism?

F. J. Diaz
1   Department of Biostatistics, The University of Kansas Medical Center, ­Kansas City, KS, USA
,
C. B. Eap
2   Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neurosciences, Department of Psychiatry, Lausanne University, Hospital of Cery, Prilly-Lausanne, Switzerland
3   School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
,
N. Ansermot
2   Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neurosciences, Department of Psychiatry, Lausanne University, Hospital of Cery, Prilly-Lausanne, Switzerland
,
S. Crettol
2   Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neurosciences, Department of Psychiatry, Lausanne University, Hospital of Cery, Prilly-Lausanne, Switzerland
,
E. Spina
4   Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
,
J. de Leon
5   Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA
6   Psychiatry and Neurosciences Research Group (CTS-549), Institute of ­Neurosciences, University of Granada, Granada, Spain
› Author Affiliations
Further Information

Publication History

received 24 April 2013
revised 24 February 2014

accepted 28 February 2014

Publication Date:
24 April 2014 (online)

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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.

Key words

clozapine - pharmacokinetics - metabolism - enzyme induction - drug interactions - therapeutic drug monitoring - valproic acid - smoking - tobacco - random-effects linear model
 

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