Can Valproic Acid be an Inducer of Clozapine Metabolism?

Abstract

Introduction Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that 1) VPA is a net inducer of clozapine metabolism, and 2) 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% to 39%) after controlling for confounding variables including smoking (35% lower, 28% to 56%). Discussion Prospective studies are needed to definitively establish that VPA may 1) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and 2) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism.

Reliable clinical serum analysis with reusable electrochemical sensor: Toward point-of-care measurement of the antipsychotic medication clozapine

“…Norclozapine has biological activity (Li et al, 2005; Olianas et al, 2009; Weiner et al, 2004) and clinicians sometimes measure the sum of clozapine and norclozapine as a “total clozapine” level (total clozapine level is shown in Figure 1a) (Diaz et al, 2014). We observed no significant differences in the DPVs between clozapine and norclozapine (Figure S6, Supporting Information).…”

The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part I: A summary of the current state for clinicians

“…The author has been conducting PubMed searches in this area for more than 15 years in the process of publishing 1) review articles in this area, [3][4][5][6][7][8][9] 2) studies of the effects of AED inducers in psychiatry, [10][11][12][13][14][15][16][17][18][19] and 3) a book with practical guidelines for each AED and/or mood stabilizing agent; the book has more than 1000 different references. 20 All of these were published in the context of trying to develop a comprehensive model of personalized prescription in psychiatry.…”

“…More recently, information on its inductive properties has been accumulating. VPA induces: 1) its own metabolism by inducing β-oxidation (prospective study); 102 2) CYP3A4 and P-gp gene expression (in vitro study); 103 3) possible UGT1A1 in a patient taking irinotecan (which has an active metabolite SN-38 metabolized by UGT1A1); 104 4) aripiprazole metabolism to a mild degree (prospective study), 105 5) olanzapine metabolism (case series, 106 TDM, 107 and a prospective DI study); 15 6) clozapine metabolism (case series, 108-109 prospective case, 18 and statistical model on TDM-DI studies 14,19 ); and 6) vitamin D metabolism in an in vitro study. 110 The available information on clozapine-olanzapine metabolism indicates that VPA can be an inducer and/or a competitive inhibitor.…”

Valproate for schizophrenia: ambrosia?

“…3 Valproate-clozapine pharmacokinetic interactions should be borne in mind where previous studies have showed no effect, mild inhibition, or induction of clozapine metabolism. 4 Moreover, dynamic interactions including myelosuppression, oversedation and confusion, and metabolic derangement have been reported in literature. 5 Nonetheless, mechanistically, valproate is GABA potentiator.…”