Examination of metabolic pathways and identification of human liver cytochrome P450 isozymes responsible for the metabolism of barnidipine, a calcium channel blocker

Abstract

1. In a human liver microsomal system, barnidipine was converted into three primary metabolites, an N -debenzylated product (M-1), a hydrolyzed product of the benzylpyrrolidine ester (M-3) and an oxidized product of the dihydropyridine ring (M-8). 2. InvolvementofCYP3Ainthethree primarymetabolic pathways was revealedbythe following studies: (a) inhibition of CYP3A, (b) a correlation study using 10 individual human liver microsomes and (c) cDNA-expression studies.Thesecondarymetabolites, M-2 and M-4 (pyridine forms of M-1 and M-3),were most likely generated from M-8 but were unlikely from M-1 or M-3. Involvement of CYP3A in the secondary pathways of metabolism is also suggested. 3. The possibility of interactions between barnidipine and coadministered drugs was examined in vitro. The formation rate of the primary metabolites was little affected by warfarin, theophylline, phenytoin, diclofenac and amitriptyline at concentrations of 200 μM, but was inhibited by glibenclamide, simvastatin and cyclosporin A. IC₅₀ for the latter drugs was estimated to be > 200, 200 and 20 μM respectively, which was roughly > 200,6000 and 50 times higher than their respective therapeutic plasma levels,suggesting that interactions with cyclosporin A, a CYP3A inhibitor, are of possible clinical relevance.