Differential impact of the CYP3A5*1 and CYP3A5*3 alleles on pre-dose concentrations of two tacrolimus formulations
Differential impact of the CYP3A5*1 and CYP3A5*3 alleles on pre-dose concentrations of two tacrolimus formulations
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DOI：
10.1097/fpc.0b013e32833ea085
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发表时间：
2011-04-01
影响因子：
2.6
通讯作者：
Budde, Klemens
中科院分区：
文献类型：
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作者：
Wehland, Markus;Bauer, Steffen;Budde, Klemens
目的研究从每日两次(P-Tac)转换为每日一次(A-Tac)他克莫司(Tac)的药代动力学和药物遗传学意义。方法分析41例肾移植患者转换前后1年内移植肾功能稳定的Tac水平。结果转换后，尽管剂量相似，患者的Tac谷值和剂量标准化谷值均显著降低(分别为14%，P=0.0004和23%，P=0.001)。与*1/*3名患者(n=13)相比，CYP3A5*3/*3名患者(n=27)在两种剂型下达到Tac目标水平(P-Tac 39%，P=0.011；A-Tac 36%，P=0.003)所需的Tac剂量显著降低。有趣的是，转换后，*1/*3例患者的平均Tac谷值和剂量归一化谷值几乎保持不变，而*3/*3例患者的平均Tac谷值和剂量归一化谷值显著下降(16%，P=0.001和25%，P=0.006)。结论本研究进一步证明了CYP3A5*1/*3基因多态性对Tac药代动力学有显著影响。此外，我们首次在两种不同的Tac配方上显示了药物遗传效应，因为*3/*3名患者的Tac谷值在转换为相同剂量的A-Tac后显著下降。药物遗传学和基因组学21：179-184(C)2011 Wolters Kluwer Health|Lippincott Williams&Wilkins。
Objectives We investigated the pharmacokinetic and pharmacogenetic implications of conversion from a twice-daily (P-Tac) to a once-daily (A-Tac) tacrolimus (Tac) formulation.Methods We analyzed Tac levels in a cohort of 41 renal transplant patients with a stable graft function over a period of 1 year before and after conversion.Results After conversion, the patients had, on average, significantly lower Tac trough and dose-normalized trough levels (14%, P=0.0004 and 23%,P=0.001, respectively) despite similar doses. CYP3A5*3/*3 patients (n=27) required significantly lower Tac doses with both the formulations to reach Tac target levels (P-Tac 39%, P=0.011; A-Tac 36%, P=0.003) compared with *1/*3 patients (n=13). Interestingly, after the conversion, mean Tac trough levels and dose-normalized trough level remained almost constant in *1/*3 patients, but decreased significantly in *3/*3 patients (16%, P=0.001 and 25%, P=0.006).Conclusion This study provides further evidence that the CYP3A5*1/*3 polymorphism significantly impacts Tac pharmacokinetics. Moreover, we show for the first time a pharmacogenetic effect on two different Tac formulations, as Tac trough levels of *3/*3 patients declined significantly after conversion to identical A-Tac doses. Pharmacogenetics and Genomics 21: 179-184 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.