EVALUATION OF THE EFFECT OF FLUXETINE ON THE FORMATION OF CARBAMAZEPINE EPOXIDE

Fluoxetine has been reported to increase carbamazepine (CBZ) plasma concentrations and cause adverse effects. CBZ-10,11 epoxide (CBZE), the major metabolite of CBZ, contributes to the clinical effect and toxicity of CBZ. The objective of the present study was to investigate the effect of fluoxetine and its major metabolite, norfluoxetine, on CBZE formation in isolated perfused rat liver, in vitro human liver (n = 5) microsomes, and patients (n = 14), after either CBZ monotherapy or polytherapy with fluoxetine. In isolated perfused rat liver, there was no effect of fluoxetine (n = 8) or norfluoxetine (n = 6) on the formation clearance of CBZE (12.8 +/- 5.3 and 11.7 +/- 3.8 ml/min, respectively) or the intrinsic metabolic clearance of CBZ (6.6 +/- 2.7 and 6.3 +/-1.8 ml/min, respectively). Studies on human liver microsomes confirmed that neither fluoxetine or norfluoxetine inhibited formation of CBZE until concentrations were >20 times those found clinically. In support of this, there was no difference in the ratio of CBZE to CBZ plasma concentrations in patients also receiving fluoxetine when compared to patients on CBZ monotherapy; however, there was a trend toward a decrease in the apparent plasma clearance of CBZ. In conclusion, increased plasma concentrations of CBZ found when fluoxetine is added are not due to decreased formation of CBZE. Clinically, if fluoxetine causes an increase in CBZ levels, CBZE plasma concentrations will increase proportionately and contribute to the toxicity.