Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
Transplantation. 2010 Dec 27;90(12):1394-400. doi: 10.1097/TP.0b013e3181fa93a4.
Tacrolimus is a major immunosuppressant, which has a narrow therapeutic range and wide interindividual variation. The effects of genetic polymorphisms of cytochrome P450 3A (CYP3A) 5 and Adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) genes on the achievement of target tacrolimus trough levels and clinical outcomes in renal transplants were evaluated.
A total of 62 patients participated in this prospective study. After an initial fixed oral dose (0.08 mg/kg two times per day), tacrolimus doses were adjusted to a target range based on daily measurement of blood trough concentration. Every patient underwent 10-day scheduled biopsy. Both the patients and investigators were blinded for the genetic polymorphisms.
Those subjects expressing CYP3A5 (n=29) evidenced significantly lower tacrolimus trough levels between days 1 and 5 after transplantation, when compared with nonexpressers (n=33). Significantly higher overall incidences of early T-cell-mediated rejection (TCR) of at least Banff grade 1 in severity (P=0.017), including clinical rejection within 10 days and subclinical rejection in biopsies at postoperative day 10 were detected in CYP3A5 expressers. The severity of TCR according to Banff '07 classification was associated with CYP3A5 genotypes (P=0.012). Moreover, multivariate analysis identified CYP3A5 expression as an independent risk factor for TCR (odds ratio: 2.79; P=0.043). Significantly lower estimated glomerular filtration rates until 1 month and numerically lower estimated glomerular filtration rates by 12 months were noted in the CYP3A5 expressers. The genetic polymorphisms of the ABCB1 genes exerted no significant effects.
We confirmed the significant effects of CYP3A5 polymorphism on the achievement of target tacrolimus trough levels and the development of acute rejection in early period after transplantation and consequent renal allograft function.
他克莫司是一种主要的免疫抑制剂，其治疗范围狭窄，个体间差异较大。本研究评估了细胞色素 P450 3A（CYP3A）5 和三磷酸腺苷结合盒亚家族 B 成员 1（ABCB1）基因的遗传多态性对肾移植受者达到目标他克莫司谷浓度和临床结局的影响。
共有 62 例患者参与了这项前瞻性研究。在初始固定口服剂量（0.08mg/kg，每天两次）后，根据每日血药谷浓度的测定结果调整他克莫司剂量，使其达到目标范围。每位患者均进行了为期 10 天的计划活检。患者和研究者均对遗传多态性不知情。
与无表达者（n=33）相比，表达 CYP3A5（n=29）的患者在移植后第 1 至 5 天的他克莫司谷浓度明显较低。在 CYP3A5 表达者中，更频繁地观察到严重程度至少为 Banff 1 级的早期 T 细胞介导排斥反应（TCR）（P=0.017），包括术后第 10 天内的临床排斥反应和活检中的亚临床排斥反应。根据 Banff '07 分类的 TCR 严重程度与 CYP3A5 基因型相关（P=0.012）。此外，多变量分析确定 CYP3A5 表达是 TCR 的独立危险因素（比值比：2.79；P=0.043）。在 CYP3A5 表达者中，直到 1 个月时的估算肾小球滤过率明显降低，并且在 12 个月时的估算肾小球滤过率数值降低。ABCB1 基因的遗传多态性没有产生显著影响。
我们证实了 CYP3A5 多态性对移植后早期达到目标他克莫司谷浓度和急性排斥反应的发展以及随后的肾移植功能的显著影响。
