The effects of the SLCO2B1 c.1457C>T polymorphism and apple juice on the pharmacokinetics of fexofenadine and midazolam in humans

被引:140
作者
Imanaga, Junko [1 ]
Kotegawa, Tsutomu [1 ]
Imai, Hiromitsu [1 ]
Tsutsumi, Kimiko [2 ]
Yoshizato, Tsuneaki [1 ]
Ohyama, Tetsuji [1 ]
Shirasaka, Yoshiyuki [3 ]
Tamai, Ikumi [3 ]
Tateishi, Tomonori [4 ]
Ohashi, Kyoichi [1 ]
机构
[1] Oita Univ, Fac Med, Dept Clin Pharmacol & Therapeut, Yufu, Oita 8795593, Japan
[2] Oita Univ, Fac Med, Dept Pharmaceut Med, Yufu, Oita 8795593, Japan
[3] Kanazawa Univ, Inst Med Pharmaceut & Hlth Sci, Fac Pharm, Kanazawa, Ishikawa, Japan
[4] Hirosaki Univ, Sch Med, Dept Clin Pharmacol, Hirosaki, Aomori 036, Japan
关键词
apple juice; fexofenadine; midazolam; SLCO2B1; FRUIT JUICES; GRAPEFRUIT JUICE; DRUG DISPOSITION; OATP-B; TRANSPORTERS; IMPACT; INHIBIT; MEMBERS; PLASMA; CYP3A;
D O I
10.1097/FPC.0b013e32834300cc
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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.
引用
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页码:84 / 93
页数:10
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