Effect of lansoprazole and rabeprazole on tacrolimus pharmacokinetics in healthy volunteers with CYP2C19 mutations
Effect of lansoprazole and rabeprazole on tacrolimus pharmacokinetics in healthy volunteers with CYP2C19 mutations
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DOI：
10.1211/0022357043914
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发表时间：
2004-08-01
影响因子：
3.3
通讯作者：
Kohda, Y
中科院分区：
文献类型：
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作者：
Itagaki, F;Homma, M;Kohda, Y
本研究旨在研究质子泵抑制剂（PPI）兰索拉唑和雷贝拉唑对细胞色素P450（CYP）2C 19基因（CYP 2C 19）突变的健康志愿者中他克莫司药代动力学的影响。在19例健康受试者中进行了一项开放标签交叉研究。他克莫司（2 mg）口服给药，伴或不伴兰索拉唑（30 mg/天，持续4天）或雷贝拉唑（10 mg/天，持续4天）。在给药前和给药后1、2、4和8 h测定他克莫司的血药浓度。通过聚合酶链反应-限制性片段长度多态性方法进行CYP 2C 19基因分型。与兰索拉唑联合给药显著降低了口服他克莫司的清除率，导致血药浓度-时间曲线下面积（AUC（0-8））增加（对照组vs兰索拉唑组：29.7 +/- 3.5 vs 44.1 +/- 5.0 ng h mL（-1），P < 0.05）。由于CYP 2C 19基因型状态，兰索拉唑对他克莫司AUC（0-8）的影响存在较大的个体差异。在有和无CYP 2C 19突变等位基因的受试者中，他克莫司AUC（0-8）的百分比变化分别为81%和29%。同时给予雷贝拉唑也增加了他克莫司的平均AUC（0-8），但差异无统计学意义。这些观察结果表明，他克莫司和兰索拉唑之间的药物相互作用发生在兰索拉唑血药浓度较高的受试者中，与CYP 2C 19遗传状态相对应。相比之下，无论CYP 2C 19基因型状态如何，雷贝拉唑对他克莫司药代动力学的影响极小。
The aim of this study was to investigate the effects of the proton pump inhibitors (PPIs), lansoprazole and rabeprazole, on tacrolimus pharmacokinetics in healthy volunteers with mutations in the cytochrome P450 (CYP) 2C19 gene (CYP2C19). An open-label crossover study was performed with 19 healthy subjects. Tacrolimus (2 mg) was administered orally with and without lansoprazole (30 mg per day for 4 days) or rabeprazole (10 mg per day for 4 days). Blood concentrations of tacrolimus were determined before and 1, 2, 4 and 8 h after dosing. Genotyping for CYP2C19 was conducted by a polymerase chain reaction-restriction fragment length polymorphism method. Coadministration of lansoprazole significantly decreased the oral tacrolimus clearance, resulting in an increase in the area under the blood concentration-time curve (AUC(0-8)) (control vs with lansoprazole: 29.7 +/- 3.5 vs 44.1 +/- 5.0 ng h mL(-1), P < 0.05). Large individual variation was observed in the effects of lansoprazole on tacrolimus AUC(0-8) owing to CYP2C19 genotype status. The percent change for tacrolimus AUC(0-8) in subjects with and without CYP2C19 mutant alleles was 81% and 29%, respectively. Coadministration of rabeprazole also increased the mean AUC(0-8) of tacrolimus, but the difference was not statistically significant. These observations suggest that drug interaction between tacrolimus and lansoprazole occurs in subjects with higher lansoprazole blood concentrations corresponding to CYP2C19 genetic status. In contrast, rabeprazole has minimal effect on tacrolimus pharmacokinetics regardless of CYP2C19 genotype status.