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

Fluoxetine has been reported to increase carbamazepine (CBZ) plasma co ncentrations and cause adverse effects. CBZ-10,11 epoxide (CBZE), the major metabolite of CBZ, contributes to the clinical effect and toxici ty of CBZ. The objective of the present study was to investigate the e ffect of fluoxetine and its major metabolite, norfluoxetine, on CBZE f ormation in isolated perfused rat liver, in vitro human liver (n = 5) microsomes, and patients (n = 14), after either CBZ monotherapy or pol ytherapy with fluoxetine. In isolated perfused rat liver, there was no effect of fluoxetine (n = 8) or norfluoxetine (n = 6) on the formatio n clearance of CBZE (12.8 +/- 5.3 and 11.7 +/- 3.8 ml/min, respectivel y) or the intrinsic metabolic clearance of CBZ (6.6 +/- 2.7 and 6.3 +/ -1.8 ml/min, respectively). Studies on human liver microsomes confirme d that neither fluoxetine or norfluoxetine inhibited formation of CBZE until concentrations were >20 times those found clinically. In suppor t 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 decre ase in the apparent plasma clearance of CBZ. In conclusion, increased plasma concentrations of CBZ found when fluoxetine is added are not du e to decreased formation of CBZE. Clinically, if fluoxetine causes an increase in CBZ levels, CBZE plasma concentrations will increase propo rtionately and contribute to the toxicity.