Identification of the human cytochrome P450s responsible for the in vitro metabolism of a leukotriene B4 receptor antagonist, CP-195,543

1. The major human cytochrome P450 (CYP) form(s) responsible for the metabolism of CP-195,543, a potent leukotriene B4 antagonist, were investigated.2. Incubation of CP-195,543 with human liver microsomes resulted in the formation of three major metabolites, M1–3. M1 and M2 were diastereoisomers and formed by oxidation on the benzylic position. M3 was formed by aromatic oxidation of the benzyl group attached to the 3-position of the benzopyran ring.3. The results from experiments with recombinant CYPs, correlation studies and inhibition studies with form-selective inhibitors and a CYP3A antibody strongly suggest that the CYP3A4 plays a major role in the metabolism of CP-195,543. Recombinant CYP3A5 did not metabolize CP-195,543.4. The apparent Km and Vmax for the formation of M1–3 in human liver microsomes were determined as 36 μM and 4.1 pmol min−1 pmol−1 P450, 44 μM and 10 pmol min−1 pmol−1 P450, and 34 μM and 2.0 pmol min−1 pmol−1 P450, respectively. The average in vitro intrinsic clearance for M2 was t...