IDENTIFICATION OF CYTOCHROMES P450 INVOLVED IN THE HUMAN LIVER MICROSOMAL METABOLISM OF THE THROMBOXANE A, INHIBITOR SERATRODAST (ABT-001)

Seratrodast (ABT-001, AA-2414) undergoes cytochrome P450 (CYP)-depende nt metabolism to a major (5-methylhydroxy seratrodast; 5-HOS) and a mi nor 4'-hydroxy seratrodast metabolite in human liver microsomes. The m ean apparent K-m and V-max for the formation of 5-HOS were 15.5 mu M a nd 589.0 pmol 5-HOS formed/mg protein/min, respectively. Chemical inhi bition using isoform-selective CYP inhibitors, correlation of 5-HOS fo rmation with several isoform-specific CYP activities in a panel of liv er microsomes, metabolism by microsomes derived from CYP cDNA-expresse d B-lymphoblastoid cells, and immunoinhibition by isoform-specific ant i-CYP antibodies indicated that 5-HOS formation is catalyzed by CYP3A and CYP2C9/10, with a minor contribution from CYP2C8 and CYP2C19, At c linically relevant concentrations, seratrodast was found to inhibit to lbutamide methylhydroxylation (IC50 = 60 mu M), (S)-mephenytoin 4'-hyd roxylation (IC50 = 50 mu M), and coumarin 7-hydroxylation (IC50 = 95 m u M), indicating the potential for significant clinical interactions. The inducers of CYP3A and/or CYP2C9 (e.g. rifampicin and phenytoin) ar e likely to alter the disposition of seratrodast.