@article {Machinist970, author = {Joseph M. Machinist and Michael D. Mayer and Ellen M. Roberts and Bruce W. Surber and A. David Rodrigues}, title = {Identification of the Human Liver Cytochrome P450 Enzymes Involved in the In Vitro Metabolism of a Novel 5-Lipoxygenase Inhibitor}, volume = {26}, number = {10}, pages = {970--976}, year = {1998}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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{\textendash}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 {\textpm} 0.8vs. 0.17 {\textpm} 0.06 μl/min/mg, mean {\textpm} 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{\textendash}67\%, and sulfaphenazole (CYP2C9-selective) decreased activity by 10{\textendash}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{\textendash}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}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/26/10/970}, eprint = {https://dmd.aspetjournals.org/content/26/10/970.full.pdf}, journal = {Drug Metabolism and Disposition} }