ABSTRACT: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 (؊)-␣ and (؉)-␣ 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 (؊)-␣ isomer was similar to those from the (؉)-␣ isomer (1.9 ؎ 0.1 versus 2.3 ؎ 2.3 l/min/pmol P450 and 0.5 ؎ 0.2 versus 0.6 ؎ 0.6 l/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 the N-debenzylation and dehydrogenation of benidipine are mainly mediated by CYP3A4 and CYP3A5. The total CL int values of CYP3A4-mediated metabolite formation from (؊)-␣ isomer were similar to those from (؉)-␣ isomer (17.7 versus 14.4 l/min/pmol P450, respectively). The total CL int values of CYP3A5-mediated metabolite formation from (؊)-␣ isomer were also similar to those from (؉)-␣ isomer (8.3 versus 11.0 l/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.Benidipine is a highly potent dihydropyridine calcium antagonist that is used clinically as a racemate. This agent shows slow onset and long-lasting antihypertensive and antianginal effects owing to the blockade of calcium ion entry to smooth muscle Yamada et al., 1990). It is currently in clinical use for the treatment of hypertension as a single daily medication (2-8 mg). Like other dihydropyridine calcium antagonists (except nifedipine and mepirodipine), benidipine has asymmetric carbons both in the 1,4-dihydropyridine ring and in the side chain of the benzylpiperidine ring. This drug is a racemate consisting of two optical isomers [(ϩ)-␣ and (Ϫ)-␣ isomer] of the four possible optical isomers because the other isomers are removed during the crystallization step on synthesis (Kobayashi and Kobayashi, 1998). The (ϩ)-␣ isomer was 30-to 100-fold more active than the (Ϫ)-␣ isomer in terms of the antihypertensive effect after i.v. administration to the spontaneously hypertensive rat (Muto et al., 1988).Pharmacokinetic studies in rats (Kobayashi and Kobayashi, 1998) and humans (Kobayashi et al., 1997) have shown that benidipine is we...

1. The metabolites of fimasartan (FMS), a new angiotensin II receptor antagonist, were characterized in human liver microsomes (HLM) and human subjects. 2. We developed a method for a simultaneous quantitative and qualitative analysis using predictive multiple reaction monitoring information-dependent acquisition-enhanced product ion scanning. To characterize metabolic reactions, FMS metabolites were analyzed using quadrupole-time of flight mass spectrometer in full-scan mode. 3. The structures of metabolites were confirmed by comparison of chromatographic retention times and mass spectra with those of authentic metabolite standards. 4. In the cofactor-dependent microsomal metabolism study, the half-lives of FMS were 56.7, 247.9 and 53.3 min in the presence of NADPH, UDPGA and NADPH + UDPGA, respectively. 5. The main metabolic routes in HLM were S-oxidation, oxidative desulfuration, n-butyl hydroxylation and N-glucuronidation. 6. In humans orally administered with 120 mg FMS daily for 7 days, the prominent metabolites were FMS S-oxide and FMS N-glucuronide in the 0-8-h pooled plasma sample of each subject. 7. This study characterizes, for the first time, the metabolites of FMS in humans to provide information for its safe use in clinical medicine.