Effect ofABCB1(MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects

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Abstract
Aim: We aimed to investigate the effect of theABCB1gene on the pharmacokinetics of amlodipine.Methods: Based on polymorphisms of theABCB1gene 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 toABCB1genotype.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/3435CCvs.2677GT/3435CT 12.0, 105.6,P < 0.01; 2677GG/3435CCvs.2677TT/3435TT 19.6, 116.0,P < 0.01; 2677GT/3435CTvs.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 betweenABCB1genotype groups (95% CI on the difference, 2677GG/3435CCvs.2677GT/3435CT − 21.5, − 0.3,P < 0.05; 2677GG/3435CCvs.2677TT/3435TT − 23.8, − 2.0,P < 0.05).Conclusion: Amlodipine pharmacokinetics was affected by the genetic polymorphisms of theABCB1gene 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 polymorphicABCB1gene paradoxically reduces the plasma levels of amlodipine. Further evaluation is thus warranted.