Characterization of benidipine and its enantiomers' metabolism by human liver cytochrome P450 enzymes.
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 (-)-alpha and (+)-alpha 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 (CL(int)) of the formation of N-desbenzylbenidipine and dehydrobenidipine metabolites from (-)-alpha isomer was similar to those from the (+)-alpha isomer (1.9 +/- 0.1 versus 2.3 +/- 2.3 microl/min/pmol P450 and 0.5 +/- 0.2 versus 0.6 +/- 0.6 microl/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 CL(int) values of CYP3A4-mediated metabolite formation from (-)-alpha isomer were similar to those from (+)-alpha isomer (17.7 versus 14.4 microl/min/pmol P450, respectively). The total CL(int) values of CYP3A5-mediated metabolite formation from (-)-alpha isomer were also similar to those from (+)-alpha isomer (8.3 versus 11.0 microl/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.
Yoon
Yune-Jung
YJ
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, 633-165, Gaegum-Dong, Busanjin-Gu, Busan 614-735, South Korea.
Kim
Kwon-Bok
KB
Kim
Hyunmi
H
Seo
Kyung-Ah
KA
Kim
Ho-Sook
HS
Cha
In-June
IJ
Kim
Eun-Young
EY
Liu
Kwang-Hyeon
KH
Shin
Jae-Gook
JG
D001711:Biotransformation; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D003627:Data Interpretation, Statistical; D004095:Dihydropyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D011335:Proadifen / Q000494:pharmacology; D013237:Stereoisomerism
D002121:Calcium Channel Blockers; D018076:DNA, Complementary; D004095:Dihydropyridines; D007527:Isoenzymes; C061004:benidipine; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen