Reduction in serum concentration of valproic acid secondary to the intake of ibuprofen as an example of valproic acid auto-induction metabolism

Abstract

Introduction. In 1998, an unexplained drug-drug interaction between valproic acid (VPA) and ibuprofen was reported. VPA has been considered a moderate inhibitor of several metabolic enzymes, but recently its inductive properties have been described, including the possibility of auto-induction. Ibuprofen can displace VPA from the plasmatic protein, increasing its serum free concentration, and subsequently its pharmacological actions, including auto-induction. The objective of this article is to describe a similar case and to contribute to the clarification of the underlying pharmacokinetic mechanisms.

Methods. A 29-year-old Spanish Caucasian male with schizophrenia was followed with steady-state trough serum concentrations of VPA and clozapine for 5 years, including 3 ibuprofen trials. The main outcome variable was the concentration-to-dose (C/D) ratio, a measure of the ability to eliminate a drug. Independent sample Mann-Whitney U tests were performed to compare C/D ratios.

Results. Five VPA C/D ratios, contaminated by VPA auto-induction occurring during or shortly after the two latter ibuprofen trials, were significantly lower (p<0.001) than the other 34 VPA C/D ratios of VPA not contaminated by auto-induction. During the highest ibuprofen dose in the third trial, the patient had two very low clozapine C/D ratios, which were significantly lower than the other 26 clozapine C/D ratios (p=0.021).

Conclusions. Reduction in total VPA concentrations could be explained by ibuprofen displacing VPA from the plasma proteins, increasing the serum free VPA. This may induce the metabolism of VPA (and clozapine) and subsequently decrease their serum total concentrations.