RT Journal Article SR Electronic T1 Identification of the Human Liver Cytochrome P450 Enzymes Involved in the In Vitro Metabolism of a Novel 5-Lipoxygenase Inhibitor JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 970 OP 976 VO 26 IS 10 A1 Machinist, Joseph M. A1 Mayer, Michael D. A1 Roberts, Ellen M. A1 Surber, Bruce W. A1 Rodrigues, A. David YR 1998 UL http://dmd.aspetjournals.org/content/26/10/970.abstract AB In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) forms involved in the oxidative metabolism of [14C]ABT-761 and itsN-dehydroxylated metabolite, [14C]ABT-438, by human liver microsomes. The two compounds were metabolized by parallel pathways, to form the corresponding methylene bridge hydroxy metabolites. There was no evidence of sulfoxidation and/or ring hydroxylation. Over the ABT-761 and ABT-438 concentration ranges studied (1–300 μM), the rate of NADPH-dependent hydroxylation was linear with respect to substrate concentration ([S]) and did not conform to saturable Michaelis-Menten kinetics. Under these conditions ([S] <KM ), the intrinsic clearance (Vmax/KM ) of ABT-438 was 10-fold higher than that of ABT-761 (1.7 ± 0.8vs. 0.17 ± 0.06 μl/min/mg, mean ± SD,N = 3 livers). The hydroxylation of both compounds was shown to be highly correlated (r = 0.83,p < 0.01, N = 11 different human livers) with CYP3A-selective erythromycin N-demethylase activity, and the correlation between ABT-761 hydroxylation and tolbutamide hydroxylase (CYP2C9-selective) activity (r= 0.63, p < 0.05, N = 10) was also statistically significant. Ketoconazole (2.0 μM), a CYP3A-selective inhibitor, inhibited the hydroxylation of both compounds by 53–67%, and sulfaphenazole (CYP2C9-selective) decreased activity by 10–20%. By comparison, α-naphthoflavone, a known activator of CYP3A, stimulated the hydroxylation of ABT-761 (8-fold) and ABT-438 (4-fold). In addition, the abundance-normalized rates of cDNA-expressed CYP-dependent metabolism indicated that hydroxylation was largely mediated (66–86%) by CYP3A(4). Therefore, it is concluded that the hydroxylation of ABT-761 and ABT-438 (≤10 μM) is primarily mediated by CYP3A, although CYP2C9 may play an ancillary role. The American Society for Pharmacology and Experimental Therapeutics