Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean subjects

Kyoung Ah Kim, Pil Whan Park, Ock Je Lee, Sang-Hyun Choi, Bon Hong Min, Kyung-Ho Shin, Boe Gwun Chun, Jae Gook Shin, Ji-Young Park

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Background and Objective: 1,4-Dihydropyridine calcium channel blockers, including amlodipine, are mainly metabolized by cytochrome P450 (CYP) 3A. We investigated the effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean male subjects. Methods: Forty healthy male participants were enrolled and genotyped for the CYP3A5*3 gene. Each subject ingested a 5-mg dose of amlodipine, and plasma amlodipine concentrations were measured for 144 hours after dosing. Blood pressure and pulse rate were also measured for pharmacodynamic analysis. Results: Among the 40 volunteers, 24 were CYP3A5*3/*3 carriers and 16 were CYP3A5*1 carriers (CYP3A5*1/*1 in 2 and CYP3A5*1/*3 in 14). The difference in the oral clearance of amlodipine approached statistical significance between the 2 major genotype groups, with CYP3A5*1 carriers (27.0 ± 8.2 L/h) showing 20% lower clearance than CYP3A5*3/*3 carriers (32.4 ± 10.2 L/h) (P = .063). However, the mean area under the plasma concentration-time curve of amlodipine was 200.9 ± 61.9 ng · h/mL for CYP3A5*1 carriers and 167.6 ± 45.0 ng · h/mL for CYP3A5*3/*3 carriers (P = .029). Moreover, the peak plasma concentration was significantly higher in CYP3A5*1 carriers (3.8 ± 1.1 ng/mL) than in CYP3A5*3/*3 carriers (3.1 ± 0.8 ng/mL) (P = .037). Pharmacodynamically, blood pressure and pulse rate were not significantly different between the 2 groups. Conclusions: CYP3A5*3/*3 carriers exhibited lower plasma amlodipine concentrations than CYP3A5*1 carriers. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of amlodipine and provides a plausible explanation for interindividual variability in amlodipine disposition.

Original languageEnglish
Pages (from-to)646-656
Number of pages11
JournalClinical Pharmacology and Therapeutics
Volume80
Issue number6
DOIs
Publication statusPublished - 2006 Dec 1

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Cytochrome P-450 CYP3A
Amlodipine
Healthy Volunteers
Pharmacokinetics
Genotype
Heart Rate
Blood Pressure
Calcium Channel Blockers

ASJC Scopus subject areas

  • Pharmacology

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Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean subjects. / Kim, Kyoung Ah; Park, Pil Whan; Lee, Ock Je; Choi, Sang-Hyun; Min, Bon Hong; Shin, Kyung-Ho; Chun, Boe Gwun; Shin, Jae Gook; Park, Ji-Young.

In: Clinical Pharmacology and Therapeutics, Vol. 80, No. 6, 01.12.2006, p. 646-656.

Research output: Contribution to journalArticle

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abstract = "Background and Objective: 1,4-Dihydropyridine calcium channel blockers, including amlodipine, are mainly metabolized by cytochrome P450 (CYP) 3A. We investigated the effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean male subjects. Methods: Forty healthy male participants were enrolled and genotyped for the CYP3A5*3 gene. Each subject ingested a 5-mg dose of amlodipine, and plasma amlodipine concentrations were measured for 144 hours after dosing. Blood pressure and pulse rate were also measured for pharmacodynamic analysis. Results: Among the 40 volunteers, 24 were CYP3A5*3/*3 carriers and 16 were CYP3A5*1 carriers (CYP3A5*1/*1 in 2 and CYP3A5*1/*3 in 14). The difference in the oral clearance of amlodipine approached statistical significance between the 2 major genotype groups, with CYP3A5*1 carriers (27.0 ± 8.2 L/h) showing 20{\%} lower clearance than CYP3A5*3/*3 carriers (32.4 ± 10.2 L/h) (P = .063). However, the mean area under the plasma concentration-time curve of amlodipine was 200.9 ± 61.9 ng · h/mL for CYP3A5*1 carriers and 167.6 ± 45.0 ng · h/mL for CYP3A5*3/*3 carriers (P = .029). Moreover, the peak plasma concentration was significantly higher in CYP3A5*1 carriers (3.8 ± 1.1 ng/mL) than in CYP3A5*3/*3 carriers (3.1 ± 0.8 ng/mL) (P = .037). Pharmacodynamically, blood pressure and pulse rate were not significantly different between the 2 groups. Conclusions: CYP3A5*3/*3 carriers exhibited lower plasma amlodipine concentrations than CYP3A5*1 carriers. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of amlodipine and provides a plausible explanation for interindividual variability in amlodipine disposition.",
author = "Kim, {Kyoung Ah} and Park, {Pil Whan} and Lee, {Ock Je} and Sang-Hyun Choi and Min, {Bon Hong} and Kyung-Ho Shin and Chun, {Boe Gwun} and Shin, {Jae Gook} and Ji-Young Park",
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T1 - Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean subjects

AU - Kim, Kyoung Ah

AU - Park, Pil Whan

AU - Lee, Ock Je

AU - Choi, Sang-Hyun

AU - Min, Bon Hong

AU - Shin, Kyung-Ho

AU - Chun, Boe Gwun

AU - Shin, Jae Gook

AU - Park, Ji-Young

PY - 2006/12/1

Y1 - 2006/12/1

N2 - Background and Objective: 1,4-Dihydropyridine calcium channel blockers, including amlodipine, are mainly metabolized by cytochrome P450 (CYP) 3A. We investigated the effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean male subjects. Methods: Forty healthy male participants were enrolled and genotyped for the CYP3A5*3 gene. Each subject ingested a 5-mg dose of amlodipine, and plasma amlodipine concentrations were measured for 144 hours after dosing. Blood pressure and pulse rate were also measured for pharmacodynamic analysis. Results: Among the 40 volunteers, 24 were CYP3A5*3/*3 carriers and 16 were CYP3A5*1 carriers (CYP3A5*1/*1 in 2 and CYP3A5*1/*3 in 14). The difference in the oral clearance of amlodipine approached statistical significance between the 2 major genotype groups, with CYP3A5*1 carriers (27.0 ± 8.2 L/h) showing 20% lower clearance than CYP3A5*3/*3 carriers (32.4 ± 10.2 L/h) (P = .063). However, the mean area under the plasma concentration-time curve of amlodipine was 200.9 ± 61.9 ng · h/mL for CYP3A5*1 carriers and 167.6 ± 45.0 ng · h/mL for CYP3A5*3/*3 carriers (P = .029). Moreover, the peak plasma concentration was significantly higher in CYP3A5*1 carriers (3.8 ± 1.1 ng/mL) than in CYP3A5*3/*3 carriers (3.1 ± 0.8 ng/mL) (P = .037). Pharmacodynamically, blood pressure and pulse rate were not significantly different between the 2 groups. Conclusions: CYP3A5*3/*3 carriers exhibited lower plasma amlodipine concentrations than CYP3A5*1 carriers. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of amlodipine and provides a plausible explanation for interindividual variability in amlodipine disposition.

AB - Background and Objective: 1,4-Dihydropyridine calcium channel blockers, including amlodipine, are mainly metabolized by cytochrome P450 (CYP) 3A. We investigated the effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean male subjects. Methods: Forty healthy male participants were enrolled and genotyped for the CYP3A5*3 gene. Each subject ingested a 5-mg dose of amlodipine, and plasma amlodipine concentrations were measured for 144 hours after dosing. Blood pressure and pulse rate were also measured for pharmacodynamic analysis. Results: Among the 40 volunteers, 24 were CYP3A5*3/*3 carriers and 16 were CYP3A5*1 carriers (CYP3A5*1/*1 in 2 and CYP3A5*1/*3 in 14). The difference in the oral clearance of amlodipine approached statistical significance between the 2 major genotype groups, with CYP3A5*1 carriers (27.0 ± 8.2 L/h) showing 20% lower clearance than CYP3A5*3/*3 carriers (32.4 ± 10.2 L/h) (P = .063). However, the mean area under the plasma concentration-time curve of amlodipine was 200.9 ± 61.9 ng · h/mL for CYP3A5*1 carriers and 167.6 ± 45.0 ng · h/mL for CYP3A5*3/*3 carriers (P = .029). Moreover, the peak plasma concentration was significantly higher in CYP3A5*1 carriers (3.8 ± 1.1 ng/mL) than in CYP3A5*3/*3 carriers (3.1 ± 0.8 ng/mL) (P = .037). Pharmacodynamically, blood pressure and pulse rate were not significantly different between the 2 groups. Conclusions: CYP3A5*3/*3 carriers exhibited lower plasma amlodipine concentrations than CYP3A5*1 carriers. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of amlodipine and provides a plausible explanation for interindividual variability in amlodipine disposition.

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