肾移植受者CYP3A5基因多态性对他克莫司血药浓度及疗效的影响*

背景：关于欧美人群中CYP3A5基因与他克莫司血药浓度之间关系已有报道，然而这些研究的数据多来自于移植后1个   月~1年，缺乏移植后早期的资料。目的：探讨CYP3A 基因多态性与肾移植受者他克莫司血药浓度的关系，分析CYP3A5基因型对肾移植后排斥反应和毒性及不良反应的影响。方法：按CYP3A5基因多态性将45例采用他克莫司+霉酚酸酯+泼尼松三联免疫抑制方案的肾移植患者分为*1/*1型组(11例)、*1/*3型组(15例)和*3/*3型组(19例)，他克莫司初始剂量均为0.15 mg/(kg•d)，1周后根据目标浓度调整他克莫司剂量。结果与结论：术后7 d，1个月，3个月* 3/* 3型组他克莫司血药浓度/剂量比显著高于* 1/*3型组和*1/*1型组(P < 0.05) ；3个月内*1/*1型组急性排斥反应的比例显著高于*1/*3型组和*3/*3型组(P < 0.05)。3个月内*3/*3型组高血糖、神经及肾毒性等不良反应显著高于*1/*1型组。结果可见*1/*1基因型患者在肾移植早期难以达到有效目标血药浓度，使该组3个月内的急性排斥反应发生率明显升高，不合适采用目前他克莫司的初始剂量方案作为早期的抗排斥反应方案；*3/*3基因型患者他克莫司血药浓度明显升高，使3个月内毒性及不良反应发生率也明显升高。因此，根据CYP3A5 基因多态性作为他克莫司个体化用药的依据，既能使* 1 /* 1型患者早期急性排斥反应的发生率下降，又能使* 3 /*3型患者的药物不良反应减少，提高肾移植的临床效果。 

Effect of CYP3A5 genetic polymorphism on concentration and efficacy of tacrolimus in patients with kidney transplantation

BACKGROUND: There are reports relating to the relation between CYP3A5 genetype and tacrolimus concentration among European and American people in recent years, however, the data of the study available comes from the date after surgery within 1 month to 1 year and there lacks of early details. OBJECTIVE: To study the relation between CYP3A5 genetic polymorphism and tacrolimus concentration per dose in kidney transplant recipients, and to evaluate the effect of CYP3A5 genotype on the acute rejection and the adverse effect of tacrolimus after kidney transplantation. METHODS: Forty-five patients transplanted with planted cadaver kidney receiving the triple immunosuppressive (tacrolimus+mycophenolatemofetil+prednison), and the patients were divided into *1/*1 group (n=11), *1/*3 group (n=15), *3/*3 group (n=19) according to the CYP3A5 genotype. The initial dose of tacrolimus was 0.15 mg/kg per day and the dosage was adjusted according to the drug concentration to a target therapeutic window. RESULTS AND CONCLUSION: At 7 day and 1 and 3 months after operation, the concentration per dosage in the *3/*3 group was significantly higher than that in the *1/*3 group and *1/*1 group (P < 0.05); the ratio of acute rejection in *1/*1 group was significantly higher than that in the *1/*3 group and *3/*3 group within 3 months (P < 0.05); the adverse effects of tacrolimus (nephrotoxicity, hyper glycosemia, neurotoxicity) were increased in CYP3A5 *3/*3 group compared with CYP3A5 *1/*1group within 3 months. The blood concentration of tacrolimus was lowest in *1/*1 genotype group within 3 months which induced the higher acute rejection rate, so the initial dosing regimen of tacrolimus was not the suitable for the treatment of early anti-rejection, and blood concentration of tacrolimus was highest in *3/*3 genotype group within 3 months which resulting in higher adverse effects. To choose the initial tacrolimus dosage required by individual patients according to the CYP3A5 genetic polymorphism is necessary for getting better outcome and reducing acute rejection in the CYP3A5 *1/*1 group and the adverse effect of tacrolimus in the CYP3A5 *3/*3 group, and which enhances the clinical effect of kidney transplantation.