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, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0-infinity) (110%) of the parent compound brofaromine and a lower Cmax (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-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.
Feifel
N
N
Human Pharmacology Institute, Ciba-Geigy GmbH, Tübingen, Germany.
Kucher
K
K
Fuchs
L
L
Jedrychowski
M
M
Schmidt
E
E
Antonin
K H
KH
Bieck
P R
PR
Gleiter
C H
CH
D000328:Adult; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism* / Q000652:urine; D005260:Female; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000652:urine; D008996:Monoamine Oxidase Inhibitors / Q000097:blood / Q000378:metabolism* / Q000652:urine; D010641:Phenotype; D010880:Piperidines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D011802:Quinidine / Q000008:administration & dosage / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D010880:Piperidines; C085097:O-desmethylbrofaromine; C038213:brofaromine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine