Identification of cytochrome P450 enzymes responsible for N -dealkylation of a new oral erectogenic, mirodenafil

Abstract

The purpose of this paper is to characterize the cytochrome P450 (CYP) enzymes involved in the metabolism of a new oral erectogenic, mirodenafil, to a major circulating active metabolite, N-dehydroxyethyl-mirodenafil, and to investigate the inhibitory potential of mirodenafil on seven CYP enzymes in human liver microsomes. CYP3A4 was identified as the major enzyme and CYP2C8 as a minor enzyme responsible for mirodenafil N-dealkylation based on correlation analysis, inhibition studies, and cDNA-expressed CYP enzyme activities. Plasma concentrations of mirodenafil and its N-dealkylated metabolite could therefore change with co-administration of known CYP3A4 inducers or inhibitors. Mirodenafil inhibited CYP3A4, CYP2C19 and CYP2D6 activities with IC50 values of 15.6, 38.2 and 77.0 µM, respectively, in human liver microsomes. However, it is very unlikely that mirodenafil will significantly alter the clearance of other compounds metabolized by CYPs 1A2, 2A6, 2C8, 2C9, 2C19, 2D6 and 3A4 because the maximum plasma concentration of mirodenafil is 0.55 µM after oral dosing of mirodenafil (100 mg) in male volunteers.