A Systematic Review of the Effect of CYP3A5 Genotype on the Apparent Oral Clearance of Tacrolimus in Renal Transplant Recipients
A Systematic Review of the Effect of CYP3A5 Genotype on the Apparent Oral Clearance of Tacrolimus in Renal Transplant Recipients
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DOI：
10.1097/ftd.0b013e3181f3c063
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发表时间：
2010-12-01
影响因子：
2.5
通讯作者：
Levine, Marc
中科院分区：
文献类型：
--
作者：
Barry, Arden;Levine, Marc
他克莫司是肾移植中常用的免疫抑制剂。他克莫司的治疗药物监测是推荐的，因为它显示了患者间广泛的药代动力学变异性。这种变异的部分原因可能是细胞色素P450 3A5(CYP3A5)代谢的结果，而细胞色素P450 3A5只在一些成年个体中表达。细胞色素P3A5的表达与细胞色素P3A5基因相关，其中具有一个或多个野生型等位基因(CYP3A5*1)的个体被认为是CYP3A5的表达个体，而突变等位基因CYP3A5*3的纯合子个体被认为是不表达的个体。达到目标浓度所需的他克莫司剂量需求与细胞色素P3A5基因(表达与不表达)之间存在关联。他克莫司的药动学可变性是基于生物利用度和全身清除量，这是由口服表观清除量来表示的。这篇综述的重点是用系统的方法来研究肾移植受者的他克莫司的口服表观清除量是否受CYP3A5基因的影响。共有5项研究报告了在表达细胞色素P3A5和不表达细胞色素P3A5之间有明显的口服清除。研究发现，CYP3A5不表达组的加权平均口腔清除量比表达组低48%(范围为26%-65%)。这种表观口服清除量的差异可以在未来的研究中用于指导肾移植受者基于基因的他克莫司的初始剂量策略。
Tacrolimus is a commonly used immunosuppressive agent in renal transplantation. Therapeutic drug monitoring of tacrolimus is recommended because it demonstrates wide pharmacokinetic inter-patient variability. Part of that variability may be the result of metabolism by cytochrome P450 3A5 (CYP3A5), which is only expressed in some adult individuals. The expression of CYP3A5 has been linked to the CYP3A5 genotype, in which individuals with one or more wild-type allele (CYP3A5*1) are considered CYP3A5 expressors, and individuals homozygous for the mutant allele CYP3A5*3 are considered non-expressors. An association has been established between CYP3A5 genotype (expressors versus nonexpressors) and tacrolimus dose requirements to achieve target concentrations. Tacrolimus pharmacokinetic variability is based on bioavailability and systemic clearance, which are represented by apparent oral clearance. The focus of this review was to use a systematic method to investigate whether the CYP3A5 genotype has an effect on the apparent oral clearance of tacrolimus in renal transplant recipients. A total of five studies were identified that reported apparent oral clearance in CYP3A5 expressors and CYP3A5 nonexpressors. The weighted mean apparent oral clearance was found to be 48% lower in CYP3A5 nonexpressors than CYP3A5 expressors (range, 26%-65%). This difference in apparent oral clearance could be used in future studies to guide initial dosing strategies of tacrolimus in renal transplant recipients based on genotype.