RT Journal Article SR Electronic T1 Identification of Cytochromes P450 Involved in the Human Liver Microsomal Metabolism of the Thromboxane A2 Inhibitor Seratrodast (ABT-001) JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 110 OP 115 VO 25 IS 1 A1 Gondi N. Kumar A1 Erik Dubberke A1 A. David Rodrigues A1 Ellen Roberts A1 Jon F. Dennisen YR 1997 UL http://dmd.aspetjournals.org/content/25/1/110.abstract AB Seratrodast (ABT-001, AA-2414) undergoes cytochrome P450 (CYP)-dependent metabolism to a major (5-methylhydroxy seratrodast; 5-HOS) and a minor 4′-hydroxy seratrodast metabolite in human liver microsomes. The mean apparent Km andVmax for the formation of 5-HOS were 15.5 μM and 589.0 pmol 5-HOS formed/mg protein/min, respectively. Chemical inhibition using isoform-selective CYP inhibitors, correlation of 5-HOS formation with several isoform-specific CYP activities in a panel of liver microsomes, metabolism by microsomes derived from CYP cDNA-expressed B-lymphoblastoid cells, and immunoinhibition by isoform-specific anti-CYP antibodies indicated that 5-HOS formation is catalyzed by CYP3A and CYP2C9/10, with a minor contribution from CYP2C8 and CYP2C19. At clinically relevant concentrations, seratrodast was found to inhibit tolbutamide methylhydroxylation (IC50 = 60 μM), (S)-mephenytoin 4′-hydroxylation (IC50 = 50 μM), and coumarin 7-hydroxylation (IC50 = 95 μM), indicating the potential for significant clinical interactions. The inducers of CYP3A and/or CYP2C9 (e.g. rifampicin and phenytoin) are likely to alter the disposition of seratrodast. The American Society for Pharmacology and Experimental Therapeutics