ROLE OF CYTOCHROME-P4502D6 IN THE METABOLISM OF BROFAROMINE - A NEW SELECTIVE MAO-A INHIBITOR

The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, s elective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significant ly longer t1/2 (136 %) and larger AUC(0-infinity) (110 %) of the paren t compound brofaromine and a lower C(max) (69 %) and AUC (0-72 h) (40 %) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethylbrofaromine in EM treated with quinidine were similar to those of untreated PM, in cluding the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, no r the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.