Effect of ABCB1 (MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects

Kyoung Ah Kim, Pil Whan Park, Ji-Young Park

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Aim: We aimed to investigate the effect of the ABCB1 gene on the pharmacokinetics of amlodipine. Methods: Based on polymorphisms of the ABCB1 gene at positions 2677 and 3435, 26 healthy male participants were divided into three groups: subjects with 2677GG/3435CC (n = 9), 2677GT/3435CT (n = 9) and 2677TT/3435TT (n = 8). After a single-dose administration of 5 mg amlodipine, plasma concentrations of amlodipine were measured and its pharmacokinetic characteristics were compared according to ABCB1 genotype. Results: The area under the plasma concentration-time curve was significantly lower in subjects with 2677TT/3435TT (140.8 ± 35.6 ng h-1 ml-1) and 2677GT/3435CT (149.8 ± 40.1 ng h-1 ml-1) than in those with 2677GG/3435CC (208.6 ± 39.2 ng h-1 ml-1) [95% confidence interval (CI) on the difference, 2677GG/3435CC vs. 2677GT/3435CT 12.0, 105.6, P < 0.01; 2677GG/3435CC vs. 2677TT/3435TT 19.6, 116.0, P < 0.01; 2677GT/3435CT vs. 2677TT/3435TT -39.2, 57.2, P > 0.05]. The peak plasma concentrations were highest in subjects with 2677GG/3435CC (3.8 ± 0.5 ng ml-1), lower in subjects with 2677GT/3435CT (3.2 ± 0.5 ng ml-1) and 2677TT/3435TT (2.7 ± 0.5 ng ml -1) in rank and showed a significant difference between those with 2677GG/3435CC and with 2677TT/3435TT (95% CI on the difference 0.4, 2.0, P < 0.01). However, the oral clearance was higher in subjects with 2677TT/3435TT (37.7 ± 10.2 l h-1) than in those with 2677GT/3435CT (35.7 ± 9.9 l h-1) and with 2677GG/3435CC (24.8 ± 5.4 l h-1) and exhibited a significant difference between ABCB1 genotype groups (95% CI on the difference, 2677GG/3435CC vs. 2677GT/3435CT -21.5, -0.3, P < 0.05; 2677GG/3435CC vs. 2677TT/3435TT -23.8, -2.0, P < 0.05). Conclusion: Amlodipine pharmacokinetics was affected by the genetic polymorphisms of the ABCB1 gene in humans. These findings may provide a plausible explanation for interindividual variation in the disposition of amlodipine, although our study could not explain the exact mechanism(s) by which the polymorphic ABCB1 gene paradoxically reduces the plasma levels of amlodipine. Further evaluation is thus warranted.

Original languageEnglish
Pages (from-to)53-58
Number of pages6
JournalBritish Journal of Clinical Pharmacology
Volume63
Issue number1
DOIs
Publication statusPublished - 2007 Jan 1

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Amlodipine
Haplotypes
Healthy Volunteers
Pharmacokinetics
Confidence Intervals
Genotype
Genes
Gene Order
Genetic Polymorphisms

Keywords

  • ABCB1 (MDR1)
  • Amlodipine
  • P-glycoprotein
  • Pharmacogenetics
  • Pharmacokinetics
  • Polymorphism

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Effect of ABCB1 (MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects. / Kim, Kyoung Ah; Park, Pil Whan; Park, Ji-Young.

In: British Journal of Clinical Pharmacology, Vol. 63, No. 1, 01.01.2007, p. 53-58.

Research output: Contribution to journalArticle

@article{1b9ae02ae3b54beaa6c30af674a67cf1,
title = "Effect of ABCB1 (MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects",
abstract = "Aim: We aimed to investigate the effect of the ABCB1 gene on the pharmacokinetics of amlodipine. Methods: Based on polymorphisms of the ABCB1 gene at positions 2677 and 3435, 26 healthy male participants were divided into three groups: subjects with 2677GG/3435CC (n = 9), 2677GT/3435CT (n = 9) and 2677TT/3435TT (n = 8). After a single-dose administration of 5 mg amlodipine, plasma concentrations of amlodipine were measured and its pharmacokinetic characteristics were compared according to ABCB1 genotype. Results: The area under the plasma concentration-time curve was significantly lower in subjects with 2677TT/3435TT (140.8 ± 35.6 ng h-1 ml-1) and 2677GT/3435CT (149.8 ± 40.1 ng h-1 ml-1) than in those with 2677GG/3435CC (208.6 ± 39.2 ng h-1 ml-1) [95{\%} confidence interval (CI) on the difference, 2677GG/3435CC vs. 2677GT/3435CT 12.0, 105.6, P < 0.01; 2677GG/3435CC vs. 2677TT/3435TT 19.6, 116.0, P < 0.01; 2677GT/3435CT vs. 2677TT/3435TT -39.2, 57.2, P > 0.05]. The peak plasma concentrations were highest in subjects with 2677GG/3435CC (3.8 ± 0.5 ng ml-1), lower in subjects with 2677GT/3435CT (3.2 ± 0.5 ng ml-1) and 2677TT/3435TT (2.7 ± 0.5 ng ml -1) in rank and showed a significant difference between those with 2677GG/3435CC and with 2677TT/3435TT (95{\%} CI on the difference 0.4, 2.0, P < 0.01). However, the oral clearance was higher in subjects with 2677TT/3435TT (37.7 ± 10.2 l h-1) than in those with 2677GT/3435CT (35.7 ± 9.9 l h-1) and with 2677GG/3435CC (24.8 ± 5.4 l h-1) and exhibited a significant difference between ABCB1 genotype groups (95{\%} CI on the difference, 2677GG/3435CC vs. 2677GT/3435CT -21.5, -0.3, P < 0.05; 2677GG/3435CC vs. 2677TT/3435TT -23.8, -2.0, P < 0.05). Conclusion: Amlodipine pharmacokinetics was affected by the genetic polymorphisms of the ABCB1 gene in humans. These findings may provide a plausible explanation for interindividual variation in the disposition of amlodipine, although our study could not explain the exact mechanism(s) by which the polymorphic ABCB1 gene paradoxically reduces the plasma levels of amlodipine. Further evaluation is thus warranted.",
keywords = "ABCB1 (MDR1), Amlodipine, P-glycoprotein, Pharmacogenetics, Pharmacokinetics, Polymorphism",
author = "Kim, {Kyoung Ah} and Park, {Pil Whan} and Ji-Young Park",
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language = "English",
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pages = "53--58",
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TY - JOUR

T1 - Effect of ABCB1 (MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects

AU - Kim, Kyoung Ah

AU - Park, Pil Whan

AU - Park, Ji-Young

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Aim: We aimed to investigate the effect of the ABCB1 gene on the pharmacokinetics of amlodipine. Methods: Based on polymorphisms of the ABCB1 gene at positions 2677 and 3435, 26 healthy male participants were divided into three groups: subjects with 2677GG/3435CC (n = 9), 2677GT/3435CT (n = 9) and 2677TT/3435TT (n = 8). After a single-dose administration of 5 mg amlodipine, plasma concentrations of amlodipine were measured and its pharmacokinetic characteristics were compared according to ABCB1 genotype. Results: The area under the plasma concentration-time curve was significantly lower in subjects with 2677TT/3435TT (140.8 ± 35.6 ng h-1 ml-1) and 2677GT/3435CT (149.8 ± 40.1 ng h-1 ml-1) than in those with 2677GG/3435CC (208.6 ± 39.2 ng h-1 ml-1) [95% confidence interval (CI) on the difference, 2677GG/3435CC vs. 2677GT/3435CT 12.0, 105.6, P < 0.01; 2677GG/3435CC vs. 2677TT/3435TT 19.6, 116.0, P < 0.01; 2677GT/3435CT vs. 2677TT/3435TT -39.2, 57.2, P > 0.05]. The peak plasma concentrations were highest in subjects with 2677GG/3435CC (3.8 ± 0.5 ng ml-1), lower in subjects with 2677GT/3435CT (3.2 ± 0.5 ng ml-1) and 2677TT/3435TT (2.7 ± 0.5 ng ml -1) in rank and showed a significant difference between those with 2677GG/3435CC and with 2677TT/3435TT (95% CI on the difference 0.4, 2.0, P < 0.01). However, the oral clearance was higher in subjects with 2677TT/3435TT (37.7 ± 10.2 l h-1) than in those with 2677GT/3435CT (35.7 ± 9.9 l h-1) and with 2677GG/3435CC (24.8 ± 5.4 l h-1) and exhibited a significant difference between ABCB1 genotype groups (95% CI on the difference, 2677GG/3435CC vs. 2677GT/3435CT -21.5, -0.3, P < 0.05; 2677GG/3435CC vs. 2677TT/3435TT -23.8, -2.0, P < 0.05). Conclusion: Amlodipine pharmacokinetics was affected by the genetic polymorphisms of the ABCB1 gene in humans. These findings may provide a plausible explanation for interindividual variation in the disposition of amlodipine, although our study could not explain the exact mechanism(s) by which the polymorphic ABCB1 gene paradoxically reduces the plasma levels of amlodipine. Further evaluation is thus warranted.

AB - Aim: We aimed to investigate the effect of the ABCB1 gene on the pharmacokinetics of amlodipine. Methods: Based on polymorphisms of the ABCB1 gene at positions 2677 and 3435, 26 healthy male participants were divided into three groups: subjects with 2677GG/3435CC (n = 9), 2677GT/3435CT (n = 9) and 2677TT/3435TT (n = 8). After a single-dose administration of 5 mg amlodipine, plasma concentrations of amlodipine were measured and its pharmacokinetic characteristics were compared according to ABCB1 genotype. Results: The area under the plasma concentration-time curve was significantly lower in subjects with 2677TT/3435TT (140.8 ± 35.6 ng h-1 ml-1) and 2677GT/3435CT (149.8 ± 40.1 ng h-1 ml-1) than in those with 2677GG/3435CC (208.6 ± 39.2 ng h-1 ml-1) [95% confidence interval (CI) on the difference, 2677GG/3435CC vs. 2677GT/3435CT 12.0, 105.6, P < 0.01; 2677GG/3435CC vs. 2677TT/3435TT 19.6, 116.0, P < 0.01; 2677GT/3435CT vs. 2677TT/3435TT -39.2, 57.2, P > 0.05]. The peak plasma concentrations were highest in subjects with 2677GG/3435CC (3.8 ± 0.5 ng ml-1), lower in subjects with 2677GT/3435CT (3.2 ± 0.5 ng ml-1) and 2677TT/3435TT (2.7 ± 0.5 ng ml -1) in rank and showed a significant difference between those with 2677GG/3435CC and with 2677TT/3435TT (95% CI on the difference 0.4, 2.0, P < 0.01). However, the oral clearance was higher in subjects with 2677TT/3435TT (37.7 ± 10.2 l h-1) than in those with 2677GT/3435CT (35.7 ± 9.9 l h-1) and with 2677GG/3435CC (24.8 ± 5.4 l h-1) and exhibited a significant difference between ABCB1 genotype groups (95% CI on the difference, 2677GG/3435CC vs. 2677GT/3435CT -21.5, -0.3, P < 0.05; 2677GG/3435CC vs. 2677TT/3435TT -23.8, -2.0, P < 0.05). Conclusion: Amlodipine pharmacokinetics was affected by the genetic polymorphisms of the ABCB1 gene in humans. These findings may provide a plausible explanation for interindividual variation in the disposition of amlodipine, although our study could not explain the exact mechanism(s) by which the polymorphic ABCB1 gene paradoxically reduces the plasma levels of amlodipine. Further evaluation is thus warranted.

KW - ABCB1 (MDR1)

KW - Amlodipine

KW - P-glycoprotein

KW - Pharmacogenetics

KW - Pharmacokinetics

KW - Polymorphism

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