Pharmacogenetic determinants for interindividual difference of tacrolimus pharmacokinetics 1 year after renal transplantation
Pharmacogenetic determinants for interindividual difference of tacrolimus pharmacokinetics 1 year after renal transplantation
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DOI：
10.1111/j.1365-2710.2010.01163.x
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发表时间：
2011-04-01
影响因子：
2
通讯作者：
Satoh, S.
中科院分区：
文献类型：
--
作者：
Miura, M.;Niioka, T.;Satoh, S.
已知与目的：他克莫司是器官移植中广泛使用的免疫抑制剂，但治疗窗较窄。研究表明，其与兰索拉唑的相互作用可能依赖于CYP 3A 5和CYP 2C 19的多态性。本研究的目的是探讨肾移植术后1年，CYP 3A 5和CYP 2C 19基因多态性，生化参数和与兰索拉唑联合给药对他克莫司药代动力学的影响。方法：在75例肾移植受者中研究他克莫司的药代动力学，这些受者均接受12小时口服他克莫司和每日30 mg兰索拉唑的持续治疗（组1; n = 20）或，10 mg雷贝拉唑每日或无质子泵抑制剂（第2组; n = 55）。经剂量调整的血药浓度-时间曲线下面积无显著差异CYP 2C 19基因型组之间他克莫司的AUC（0-12）和最大血药浓度（C-max），而CYP 3A 5基因型组间差异有统计学意义（*1/*1 + *1/*3对比 *3/*3 = 45中心点2 +/-20中心点0对比71中心点0 +/-34中心点1 ng中心点h/mL/mg，P < 0中心点0001和6中心点3 +/- 2中心点6对比9中心点3 +/- 7中心点0 ng/mL/mg，P = 0中心点0017，以及与兰索拉唑联合给药和不与兰索拉唑联合给药之间的差异（74个中心点5 +/-34个中心点0 vs. 52个中心点4 +/-27个中心点4 ng中心点h/mL/mg，分别为P = 0中心点0054和10中心点9 +/- 8中心点8对6中心点7 +/- 3中心点0 ng/mL/mg，P = 0中心点0024）。在多元回归分析中，他克莫司的剂量调整AUC（0-12）和C-max与CYP 3A 5 *3/*3和与兰索拉唑联合给药相关。新的和结论：CYP 2C 19似乎对他克莫司和兰索拉唑之间的相互作用没有贡献。他克莫司和兰索拉唑的长期联合治疗需要对CYP 3A 5 *3/*3基因型患者进行仔细监测。
P>What is known and objective:Tacrolimus, a widely used immunosuppressive agent in organ transplantation, has a narrow therapeutic window. It has been suggested that its interaction with lansoprazole could be dependent on polymorphisms of CYP3A5 and CYP2C19. The objective of this study was to investigate how, 1 year after renal transplantation, CYP3A5 and CYP2C19 polymorphisms, biochemical parameters and coadministration with lansoprazole, influenced tacrolimus pharmacokinetics.Methods:The pharmacokinetics of tacrolimus was studied 1 year after renal transplantation, in 75 recipients who were all receiving continuation treatment with 12-hourly oral tacrolimus, and 30 mg lansoprazole daily (Group 1; n = 20) or, 10 mg rabeprazole daily or no proton pump inhibitor (Group 2; n = 55).Results:There were no significant differences in the dose-adjusted area under the plasma concentration-time curve (AUC(0-12)) and maximum plasma concentration (C-max) of tacrolimus between CYP2C19 genotype groups, but there were significant differences between CYP3A5 genotypes groups (*1/*1 + *1/*3 vs. *3/*3 = 45 center dot 2 +/- 20 center dot 0 vs. 71 center dot 0 +/- 34 center dot 1 ng center dot h/mL/mg, P < 0 center dot 0001 and 6 center dot 3 +/- 2 center dot 6 vs. 9 center dot 3 +/- 7 center dot 0 ng/mL/mg, P = 0 center dot 0017, respectively) and between co-administration with and without lansoprazole (74 center dot 5 +/- 34 center dot 0 vs. 52 center dot 4 +/- 27 center dot 4 ng center dot h/mL/mg, P = 0 center dot 0054 and 10 center dot 9 +/- 8 center dot 8 vs. 6 center dot 7 +/- 3 center dot 0 ng/mL/mg, P = 0 center dot 0024, respectively). In a multiple regression analysis, the dose-adjusted AUC(0-12) and C-max of tacrolimus were associated with CYP3A5*3/*3 and co-administration with lansoprazole.What is new and conclusion:CYP2C19 does not seem to contribute to the interaction between tacrolimus and lansoprazole. The long-term combination of tacrolimus and lansoprazole requires careful monitoring of patients with the CYP3A5*3/*3 genotype.