Identification of cytochromes P450 involved in the human liver microsomal metabolism of the thromboxane A2 inhibitor seratrodast (ABT-001).

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 K(m) and Vmax for the formation of 5-HOS were 15.5 microM 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 microM), (S)-mephenytoin 4'-hydroxylation (IC50 = 50 microM), and coumarin 7-hydroxylation (IC60 = 95 microM), 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.