Interaction of Fluoxetine and Valproic Acid

TO THE EDITOR: The combination of fluoxetine and valproic acid is frequently used for psychiatric patients (i.e., those with bipolar depression). However, there is a growing recognition that the inhibitory effect of fluoxetine on cytochrome P450 may lead to serious adverse reactions (1). We report a drug interaction between fluoxetine and valproic acid.

The addition of fluoxetine to an ongoing treatment with valproic acid produced an increase in the steady-state concentrations of valproic acid. Two reports of this interaction (2, 3) have been published in the past few years, but its mechanism remains unknown. Fluoxetine has the potential risk of causing pharmacokinetic interactions with drugs metabolized by cytochrome P450 2D6 and P450 3A4 (1). However, valproic acid is mainly converted to glucuronide by hepatic enzymes, whereas the cytochrome P450-catalyzed formation of the hepatotoxic metabolite accounts for less than 10% of the dose (4). Thus, drugs that affect only cytochrome P450 enzymes are not expected to alter valproic acid clearance appreciably. The most plausible explanation for the raised valproic acid blood levels caused by fluoxetine is impaired glucuronide formation in the liver. While co-ordinate induction of glucuronyl transferases and cytochrome P450 enzymes has been demonstrated (5), we suggest that fluoxetine might inhibit both routes of metabolism. A displacement of valproic acid from plasma protein binding sites is unlikely, as fluoxetine has not been previously found to participate in this type of interaction.