RT Journal Article
SR Electronic
T1 Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1518
OP 1524
DO 10.1124/dmd.106.013607
VO 35
IS 9
A1 Yoon, Yune-Jung
A1 Kim, Kwon-Bok
A1 Kim, Hyunmi
A1 Seo, Kyung-Ah
A1 Kim, Ho-Sook
A1 Cha, In-June
A1 Kim, Eun-Young
A1 Liu, Kwang-Hyeon
A1 Shin, Jae-Gook
YR 2007
UL http://dmd.aspetjournals.org/content/35/9/1518.abstract
AB Benidipine is a dihydropyridine calcium antagonist that has been used clinically as an antihypertensive and antianginal agent. It is used clinically as a racemate, containing the (-)-α and (+)-α isomers of benidipine. This study was performed to elucidate the metabolism of benidipine and its enantiomers in human liver microsomes (HLMs) and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of benidipine. Human liver microsomal incubation of benidipine in the presence of NADPH resulted in the formation of two metabolites, N-desbenzylbenidipine and dehydrobenidipine. The intrinsic clearance (CLint) of the formation of N-desbenzylbenidipine and dehydrobenidipine metabolites from (-)-α isomer was similar to those from the (+)-α isomer (1.9 ± 0.1 versus 2.3 ± 2.3 μl/min/pmol P450 and 0.5 ± 0.2 versus 0.6 ± 0.6 μl/min/pmol P450, respectively). Correlation analysis between the known P450 enzyme activities and the rate of the formation of benidipine metabolites in the 15 HLMs showed that benidipine metabolism is correlated with CYP3A activity. The P450 isoform-selective inhibition study in liver microsomes and the incubation study of cDNA-expressed enzymes also showed that theN-debenzylation and dehydrogenation of benidipine are mainly mediated by CYP3A4 and CYP3A5. The total CLint values of CYP3A4-mediated metabolite formation from (-)-α isomer were similar to those from (+)-α isomer (17.7 versus 14.4 μl/min/pmol P450, respectively). The total CLint values of CYP3A5-mediated metabolite formation from (-)-α isomer were also similar to those from (+)-α isomer (8.3 versus 11.0 μl/min/pmol P450, respectively). These findings suggest that CYP3A4 and CYP3A5 isoforms are major enzymes contributing to the disposition of benidipine, but stereoselective disposition of benidipine in vivo may be influenced not by stereoselective metabolism but by other factors. The American Society for Pharmacology and Experimental Therapeutics