title: CYP3A is responsible for N-dealkylation of haloperidol and bromperidol and oxidation of their reduced forms by human liver microsomes.
abstract: We studied the biotransformation of haloperidol, bromperidol and their reduced forms by human liver microsomes. Nifedipine oxidation (CYP3A) activity correlated significantly with N-dealkylation rates of haloperidol and bromperidol and oxidation rates of their reduced forms, while neither ethoxyresorufin O-deethylation (CYP1A2) activity nor dextromethorphan O-deethylation (CYP2D6) activity did. In chemical and immunoinhibition studies, only troleandomycin and anti-CYP3A4 serum inhibited both formation rates of 4-fluorobenzoylpropionic acid, a metabolite of haloperidol and bromperidol, and back oxidation rates. Among 10 recombinant isoforms examined, only CYP3A4 showed catalytic activity. The Vmax and Km values of N-dealkylation of bromperidol and reoxidation of reduced bromperidol were similar to those of haloperidol and reduced haloperidol, respectively. The present study indicates that CYP3A plays a major role in N-dealkylation of and oxidation back to bromperidol as well as haloperidol and suggests that modification of in vivo CYP3A activity by inhibition or induction may affect the pharmacokinetics and therapeutic effects of haloperidol and bromperidol.
authors.affiliation: Department of Pharmacology, St. Marianna University School of Medicine, Kanagawa, Japan. tateishi@cc.hirosaki-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Tateishi
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: T
authors.initials: T
authors.lastname: Kumai
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Moriya
authors.forename: S
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: T
authors.initials: T
authors.lastname: Satoh
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D006220:Haloperidol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000276:immunology; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D011422:Propionates / Q000378:metabolism; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D011422:Propionates; C080346:beta-(4-fluorobenzoyl)propionic acid; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; D006220:Haloperidol; C006820:bromperidol