RT Journal Article SR Electronic T1 N-Dealkylation and Hydroxylation of Ebastine by Human Liver Cytochrome P450 JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 566 OP 571 VO 26 IS 6 A1 Takanori Hashizume A1 Masashi Mise A1 Yoshiaki Terauchi A1 Luan O, Toshihiko Fujii A1 Hisashi Miyazaki A1 Tadanobu Inaba YR 1998 UL http://dmd.aspetjournals.org/content/26/6/566.abstract AB Ebastine [4′-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyro phe- none] is a new-generation, nonsedative, H1antihistamine. The present study was performed to characterize the cytochrome P450 (CYP) isoforms responsible for ebastineN-dealkylation and hydroxylation. Human liver microsomes metabolized ebastine to two major metabolites, i.e. a desbutyrophenone metabolite (des-BP) and hydroxyebastine (M-OH), and the ratio of Vmax values was 3:1.N-Dealkylation yielded des-BP, whereas M-OH, an hydroxylation product, could be further oxidized to the pharmacologically active carebastine. In a panel of 14 human liver microsomal preparations, the rate of dealkylation showed a highly significant correlation with CYP3A-mediated testosterone 6β-hydroxylation but not with reactions of seven other CYP isoforms. However, there was no correlation between the two pathways for ebastine (dealkylation and hydroxylation). Differential chemical inhibition in liver microsomes, in which dealkylation was more sensitive than hydroxylation, was demonstrated with ketoconazole, troleandomycin, cyclosporin A, and midazolam. Anti-CYP3A antibodies markedly reduced the dealkylation rate (>95%) in liver microsomes but exhibited insignificant effects on hydroxylation (<5%). Among 12 cDNA-expressed human CYP isoforms, which account for up to 70% of the total CYP enzyme content in human liver, CYP3A4 alone metabolized ebastine; the ratio of des-BP to M-OH formation was 12:1. This ratio for metabolism by the pure enzyme was much larger than the ratio (3:1) observed for the microsomal reaction mixture. This change in ratio, which is attributed to a decrease in M-OH formation, indicates that, although ebastine is metabolized to two major metabolites,N-dealkylation to des-BP is mediated by CYP3A, whereas hydroxylation to M-OH appears to be mediated mainly by unidentified enzymes other than CYP3A. The American Society for Pharmacology and Experimental Therapeutics