Can valproic acid be an inducer of clozapine metabolism?
BACKGROUND
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%).


CONCLUSIONS
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.
Department of Biostatistics, The University of Kansas Medical Center, -Kansas City, KS, USA.
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Diaz
Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neurosciences, Department of Psychiatry, Lausanne University, Hospital of Cery, Prilly-Lausanne, Switzerland.
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Eap
Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neurosciences, Department of Psychiatry, Lausanne University, Hospital of Cery, Prilly-Lausanne, Switzerland.
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Ansermot
Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neurosciences, Department of Psychiatry, Lausanne University, Hospital of Cery, Prilly-Lausanne, Switzerland.
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Crettol
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
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Spina
Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA.
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de Leon
D018692:Antimanic Agents / Q000097:blood / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000031:analogs & derivatives / Q000097:blood* / Q000627:therapeutic use; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D001523:Mental Disorders / Q000097:blood* / Q000188:drug therapy*; D012737:Sex Factors; D012907:Smoking / Q000097:blood / Q000188:drug therapy; D014635:Valproic Acid / Q000097:blood / Q000627:therapeutic use*
D018692:Antimanic Agents; C058272:norclozapine; D014635:Valproic Acid; D003024:Clozapine