title: Effect of benidipine on simvastatin metabolism in human liver microsomes.
abstract: Benidipine, which is a calcium channel blocker that has clinical advantages in the treatment of hypertension, is metabolized by CYP3A4 in humans. The effect of benidipine on the metabolism of simvastatin by human liver microsomes was investigated in order to predict the potential of in vivo drug-drug interactions between benidipine and other substrates of CYP3A4. The results were compared with data generated with azelnidipine, which is also metabolized by CYP3A4. Both benidipine and azelnidipine inhibited simvastatin metabolism in vitro in a concentration-dependent manner. Assuming competitive inhibition, the K(i) values based on the unbound concentrations, were calculated to be 0.846 and 0.0181 microM for benidipine and azelnidipine, respectively. If simvastatin (10 mg) and benidipine (8 mg, the clinically recommended highest dose) were to be administered concomitantly, the ratio of the areas under the concentration-time curves of simvastatin with and without benidipine (AUC((+I))/AUC) was predicted to be 1.01. On the other hand, if simvastatin (10 mg) and azelnidipine (8 mg) were co-administered, the AUC((+I))/AUC for simvastatin was predicted to be 1.72, which is close to the observed value (1.9) in healthy volunteers. These data suggest that benidipine is unlikely to cause a drug interaction by inhibiting CYP3A4 activity in the liver.
authors.affiliation: Pharmacokinetic Research Laboratories, Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Mimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuwabara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Junko
authors.initials: J
authors.lastname: Ushiki
authors.forename: Eiichi
authors.initials: E
authors.lastname: Fuse
mesh_terms: D000465:Algorithms; D019540:Area Under Curve; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D015394:Molecular Structure; D019821:Simvastatin / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C061004:benidipine; D001383:Azetidinecarboxylic Acid; D003577:Cytochrome P-450 Enzyme System; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C061679:azelnidipine