The effects of the SLCO2B1 c.1457C>T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans
The effects of the SLCO2B1 c.1457C>T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans
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DOI：
10.1097/fpc.0b013e32834300cc
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发表时间：
2011-02-01
影响因子：
2.6
通讯作者：
Ohashi, Kyoichi
中科院分区：
文献类型：
--
作者：
Imanaga, Junko;Kotegawa, Tsutomu;Ohashi, Kyoichi
目的 探讨 SLCO2B1 c.1457C> T 多态性和苹果汁对非索非那定和咪达唑仑在人体内药代动力学的影响。方法根据 SLCO2B1 c.1457C > T 基因型划分个体（n = 14, c.[1457C] + c.[=] 5, c.[1457C]+ c.[1457C > T] 5，和 c.[1457C > T]+ c.[1457C > T] 4)。在一项随机交叉研究中，用水或苹果汁（1200 ml/天）评估了 60 mg 非索非那定和 5 mg 咪达唑仑的口服药代动力学。使用非洲爪蟾卵母细胞基因表达系统评估 OATP2B1 介导的非索非那定和咪达唑仑的摄取。 结果 当非索非那定用水给药时，与 c.[1457C] + c[=] 受试者相比，带有 c.[1457C > T] 等位基因的受试者显示非索非那定的血浆浓度-时间曲线下面积 (AUC) 显着降低 (1110 +/-) 347 与 1762 +/- 542 ng.h/ml，P < 0.05）。当与苹果汁一起服用时，与水相比，观察到非索非那定 AUC 显着降低（1342 +/- 519 vs. 284 +/- 79.2 ng.h/ml，P < 0.05）。在携带 c.[1457C > T] 等位基因的受试者中，苹果汁引起的非索非那定 AUC 降低显着较低。除了服用苹果汁后 C-max 略微显着降低外，基因型和苹果汁均未对咪达唑仑的药代动力学产生显着影响。注射OATP2B1 cRNA的卵母细胞对非索非那定的摄取显着高于注射水的卵母细胞。苹果汁而非咪达唑仑显着降低了OATP2B1 cRNA注射卵母细胞对非索非那定的摄取。结论结果表明非索非那定是OATP2B1的底物，并且OATP2B1的转运功能受SLCO2B1 c基因型的影响。 1457C > T 和苹果汁。苹果汁可能对 CYP3A 影响不大。药物遗传学和基因组学 21：84-93 (C) 2011 Wolters Kluwer Health 垂直条 Lippincott Williams & Wilkins。
Objective The objective was to determine the effects of the SLCO2B1 c.1457C> T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans.Methods Individuals were divided based on the genotype of SLCO2B1 c.1457C > T (n = 14, c.[1457C] + c.[=] 5, c.[1457C]+ c.[1457C > T] 5, and c.[1457C > T]+ c.[1457C > T] 4). The oral pharmacokinetics of 60 mg fexofenadine and 5 mg midazolam were assessed with water or apple juice (1200 ml/day) in a randomized crossover study. OATP2B1-mediated uptake of fexofenadine and midazolam was evaluated with Xenopus laevis oocyte gene-expression system.Results When fexofenadine was administered with water, subjects with c.[1457C > T] allele showed a significant decrease in fexofenadine in the area under the plasma concentration-time curve (AUC) compared with c.[1457C] + c[=] subjects (1110 +/- 347 vs. 1762 +/- 542 ng.h/ml, P < 0.05). When administered with apple juice, a significant decrease in the fexofenadine AUC was observed compared with water (1342 +/- 519 vs. 284 +/- 79.2 ng.h/ml, P < 0.05). The apple juice induced decrease in fexofenadine AUC was significantly lower in subjects carrying the c.[1457C > T] allele. Neither the genotype nor the apple juice showed significant effects on the pharmacokinetics of midazolam except for a marginally significant decrease in C-max after administration with apple juice. The uptake of fexofenadine by OATP2B1 cRNA-injected oocytes was significantly higher than that by water-injected oocytes. Apple juice, but not midazolam, significantly decreased the uptake of fexofenadine by OATP2B1 cRNA-injected oocytes.Conclusion The results suggest that fexofenadine is a substrate of OATP2B1, and the transport function of OATP2B1 is subject to the genotype of SLCO2B1 c. 1457C > T and apple juice. It is likely that apple juice has little effect on CYP3A. Pharmacogenetics and Genomics 21: 84-93 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.