FLUVOXAMINE INHIBITION AND CARBAMAZEPINE INDUCTION OF THE METABOLISM OF CLOZAPINE - EVIDENCE FROM A THERAPEUTIC DRUG-MONITORING SERVICE

Therapeutic drug monitoring data for clozapine were used to study inte ractions with other drugs. The distribution of the ratio concentration /dose (C/D) of clozapine was compared in four matched groups-patients simultaneously treated with benzodiazepines, patients on drugs that in hibit the cytochrome P450 enzyme CYP2D6, patients taking carbamazepine , and those not taking any of these drugs. No difference was seen amon g the monotherapy, CYP2D6, and benzodiazepine groups. Patients on carb amazepine had a mean 50% lower C/D than the monotherapy group (p < 0.0 01), indicating that carbamazepine is an inducer of the metabolism of clozapine. The C/D was inversely correlated to the daily dose of carba mazepine. Intraindividual comparisons in eight patients, with analyses both on and off carbamazepine, confirmed a substantial decrease of th e clozapine concentration when carbamazepine was introduced. Four pati ents treated with clozapine were concomitantly given the antidepressan t fluvoxamine. Three of them exhibited a much higher C/D ratio when on fluvoxamine compared with the monotherapy group. Two had their clozap ine levels analyzed when on and off fluvoxamine. The dose-normalized c lozapine concentration increased by a factor of 5-10 when fluvoxamine was added. We conclude that carbamazepine causes decreased clozapine p lasma levels, while fluvoxamine increases the levels. The pathways are not known with certainty, but CYP1A2 may be of major importance for t he metabolism of clozapine, since fluvoxamine is a potent inhibitor of this enzyme. A recent panel study suggests that determination of CYP1 A2 activity with the caffeine test may be very useful for the dosing o f clozapine. The induction of clozapine metabolism by carbamazepine mi ght be partly mediated by CYP3A4.