Stereoselective pharmacokinetics of dihydropyridine calcium antagonists

Tokuma, Yoji; Noguchi, Hideyo

doi:10.1016/0021-9673(94)00832-t

Cited by 54 publications

(33 citation statements)

References 73 publications

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“…[4][5][6] Biotransformation of nilvadipine occurs by almost complete oxidation of the dihydropyridine ring to form the pyridine derivative, and nilvadipine is extensively metabolized with no recovery of the unchanged drug in the urine. [7][8][9][10] It is well known that the oxidation of many dihydropyridine calcium antagonists, including nifedipine and felodipine, into corresponding pyridines are catalyzed by CYP3A4.…”

mentioning

confidence: 99%

Effect of Nilvadipine, a Dihydropyridine Calcium Antagonist, on Cytochrome P450 Activities in Human Hepatic Microsomes

Niwa

Shiraga

Hashimoto

et al. 2004

Biological & Pharmaceutical Bulletin

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mentioning

confidence: 99%

Effect of Nilvadipine, a Dihydropyridine Calcium Antagonist, on Cytochrome P450 Activities in Human Hepatic Microsomes

Niwa

Shiraga

Hashimoto

et al. 2004

Biological & Pharmaceutical Bulletin

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“…At present, only limited pharmacokinetic data of the benidipine enantiomers are available. The preliminary data from a study in humans (Tokuma and Noguchi, 1995;Kang et al, 2005) suggest that the plasma concentrations of the (ϩ)-␣ enantiomer were higher than those of the (Ϫ)-␣ enantiomer. Therefore, we evaluated the possibility of enantioselective metabolism of benidipine using HLMs and recombinant P450 isoforms as examples of felodipine (Eriksson et al, 1991) and nilvadipine (Niwa et al, 1989).…”

Section: In Vitro Metabolism Of Benidipine Enantiomersmentioning

confidence: 97%

“…at ASPET Journals on May 9, 2018 dmd.aspetjournals.org calcium antagonists, such as felodipine, nimodipine, nitrendipine, and nilvadipine, in animals and humans has been extensively reported (Niwa et al, 1988;Soons et al, 1993) and reviewed (Tokuma and Noguchi, 1995;Inotsume and Nakano, 2002). The stereoselective pharmacokinetics can be explained by the rate-limiting step of a single P450 enzyme and similar stereoselectivity for these structurally related drugs (Niwa et al, 1989;Eriksson et al, 1991).…”

Section: In Vitro Metabolism Of Benidipine Enantiomersmentioning

confidence: 99%

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

Yoon¹,

Kim²,

Kim³

et al. 2007

Drug Metab Dispos

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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...

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“…3,4 To investigate the ratio and kinetic profile of the two isradipine enantiomers in human serum, a stereoselective analytical method for isradipine was developed. (Fig.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective determination of isradipine in human serum using chiral stationary phase liquid chromatography and gas chromatography with nitrogen selective detection

1998

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Stereoselective pharmacokinetics of dihydropyridine calcium antagonists

Cited by 54 publications

References 73 publications

Effect of Nilvadipine, a Dihydropyridine Calcium Antagonist, on Cytochrome P450 Activities in Human Hepatic Microsomes

Effect of Nilvadipine, a Dihydropyridine Calcium Antagonist, on Cytochrome P450 Activities in Human Hepatic Microsomes

Characterization of Benidipine and Its Enantiomers' Metabolism by Human Liver Cytochrome P450 Enzymes

Enantioselective determination of isradipine in human serum using chiral stationary phase liquid chromatography and gas chromatography with nitrogen selective detection

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