CYP3A is responsible for N-dealkylation of haloperidol and bromperidol andoxidation of their reduced forms by human liver microsomes

We studied the biotransformation of haloperidol bromperidol and their reduc ed forms by human liver microsomes. Nifedipine oxidation (CYP3A) activity c orrelated significantly with N-dealkylation rates of haloperidol and brompe ridol and oxidation rates of their reduced forms, while neither ethoxy reso rufin O-deethylation (CYP1A2) activity nor dextromethorphan O-deethylation (CYP2D6) activity did, In chemical and immunoinhibition studies, only trole andomycin and anti-CYP3A4 serum inhibited both formation rates of 4-fluorob enzoylpropionic acid, a metabolite of haloperidol and bromperidol, and back oxidation rates. Among 10 recombinant isoforms examined, only CYP3A4 showe d catalytic activity. The Vmax and Km values of N-dealkylation of bromperid ol and reoxidation of reduced bromperidol were similar to those of haloperi dol and reduced haloperidol, respectively. The present study indicates that CYP3A plays a major role in N-dealkylation of and oxidation back to brompe ridol as well as haloperidol and suggests that modification of in vivo CYP3 A activity by inhibition or induction may affect the pharmacokinetics and t herapeutic effects of haloperidol and bromperidol. (C) 2000 Elsevier Scienc e Inc. All rights reserved.