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Interaction of Fluoxetine and Valproic Acid

Key Words: Letter

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.

Ms. A, a 26-year-old obese woman, was referred because of the weekly occurrence of generalized seizures and pseudoseizures. Treatment with valproic acid was initiated, and the dose was titrated up to 2000 mg/day. The patient's valproate serum levels were routinely monitored, and the level (78 mg/liter) was always within the therapeutic range (50–120 mg/liter). She did not receive other drugs. One year later Ms. A developed major depression with binge eating episodes. She was started on fluoxetine, 20 mg/day, and after a week the dose was increased to 40 mg/day. Partial control of symptoms was obtained within 1 month after initiation of fluoxetine, but her valproate serum level (126 mg/liter) had risen above the therapeutic range and remained essentially unchanged (131 mg/liter) 20 days later. The patient was informed about the pharmacological interaction, and she agreed to the withdrawal of fluoxetine. Subsequent serum level monitoring showed a gradual reduction of valproic acid levels (week 2: 105 mg/liter; week 3: 87 mg/liter). The patient continued to take the same dose of valproic acid, achieving good seizure control.

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.

REFERENCES

1. Nemeroff CB, DeVane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 1996; 153:311–320[Abstract/Free Full Text]
2. Sovner R, Davis JM: A potential drug interaction between fluoxetine and valproic acid (letter). J Clin Psychopharmacol 1991; 11:389[Medline]
3. Cruz-Flores S, Hayat GR, Mirza W: Valproic toxicity with fluoxetine therapy. Mo Med 1995; 92:296–297
4. Levy RH, Rettenmeier AW, Anderson GD, Wilensky AJ, Friel PN, Baillie TA, Acheampong A, Tor J, Guyot M, Loiseau P: Effects of polytherapy with phenytoin, carbamazepine, and stiri~pentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid. Clin Pharmacol Ther 1990; 48:225–235[Medline]
5. Park BK, Kitterinham NR, Pirmohamed M, Tucker GT: Relevance of induction of human drug-metabolizing enzymes: pharmacological and toxicological implications. Br J Clin Pharmacol 1996; 41:477–491[Medline]

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