源自G2677T/C3435T的ABCB1（MDR1）单倍型对健康受试者氨氯地平药代动力学的影响。
Effect of ABCB1 (MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects.
作者信息
Kim Kyoung-Ah, Park Pil-Whan, Park Ji-Young
机构信息
Department of Pharmacology, Korea University College of Medicine, Seoul, Korea.
出版信息
Br J Clin Pharmacol. 2007 Jan;63(1):53-8. doi: 10.1111/j.1365-2125.2006.02733.x. Epub 2006 Jul 21.
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.
目的
我们旨在研究ABCB1基因对氨氯地平药代动力学的影响。
方法
基于ABCB1基因第2677和3435位点的多态性，将26名健康男性参与者分为三组：2677GG/3435CC基因型受试者（n = 9）、2677GT/3435CT基因型受试者（n = 9）和2677TT/3435TT基因型受试者（n = 8）。单次服用5 mg氨氯地平后，测定氨氯地平的血浆浓度，并根据ABCB1基因型比较其药代动力学特征。
结果
2677TT/3435TT基因型受试者（140.8±35.6 ng h⁻¹ ml⁻¹）和2677GT/3435CT基因型受试者（149.8±40.1 ng h⁻¹ ml⁻¹）的血浆浓度-时间曲线下面积显著低于2677GG/3435CC基因型受试者（208.6±39.2 ng h⁻¹ ml⁻¹）[差异的95%置信区间（CI），2677GG/3435CC与2677GT/3435CT比较为12.0，105.6，P < 0.01；2677GG/3435CC与2677TT/3435TT比较为19.6，116.0，P < 0.01；2677GT/3435CT与2677TT/3435TT比较为 - 39.2，57.2，P > 0.05]。血浆峰浓度在2677GG/3435CC基因型受试者中最高（3.8±0.5 ng ml⁻¹），2677GT/3435CT基因型受试者（3.2±0.5 ng ml⁻¹）和2677TT/3435TT基因型受试者（2.7±0.5 ng ml⁻¹）依次降低，且2677GG/3435CC基因型受试者与2677TT/3435TT基因型受试者之间存在显著差异（差异的95%CI为0.4，2.0，P < 0.01）。然而，2677TT/3435TT基因型受试者的口服清除率（37.7±10.2 l h⁻¹）高于2677GT/3435CT基因型受试者（35.7±9.9 l h⁻¹）和2677GG/3435CC基因型受试者（24.8±5.4 l h⁻¹），且在ABCB1基因型组之间存在显著差异（差异的95%CI，2677GG/3435CC与2677GT/3435CT比较为 - 21.5， - 0.3，P < 0.05；2677GG/3435CC与2677TT/3435TT比较为 - 23.8， - 2.0，P < 0.05）。
结论
氨氯地平的药代动力学受人类ABCB1基因遗传多态性的影响。这些发现可能为氨氯地平处置的个体间差异提供一个合理的解释，尽管我们的研究无法解释多态性ABCB1基因反常降低氨氯地平血浆水平的确切机制。因此有必要进行进一步评估。
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