Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation
Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation
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DOI：
10.1111/j.1440-1681.2006.04492.x
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发表时间：
2006-11-01
影响因子：
2.9
通讯作者：
Zhou, Hong-Hao
中科院分区：
文献类型：
--
作者：
Hu, Yong-Fang;Qiu, Wen;Zhou, Hong-Hao
钙调神经磷酸酶抑制剂环孢霉素被广泛应用于实体器官移植术后预防同种异体移植排斥反应。它具有狭窄的治疗指数，并显示出相当大的个体间差异，其药代动力学。代谢酶细胞色素P450（CYP）3A 4和3A 5以及多药外排泵P-糖蛋白（P-gp）的活性和表达的个体间差异对环孢素的药代动力学有很大影响。CYP 3A 4、CYP 3A 5和P-gp活性的变异性可能是由其基因编码的遗传多态性引起的，本研究旨在回顾性评价CYP 3A 4、CYP 3A 5和P-gp基因编码的遗传多态性对CYP 3A 4、CYP 3A 5和P-gp活性的影响。CYP 3A 5和MDR 1对肾移植术后早期环孢素血药浓度的影响采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法检测CYP 3A 4 * 18 A、CYP 3A 5 *3和MDR 1 C3435 T基因型。采用荧光偏振免疫法测定环孢素全血浓度。CYP 3A 4 * 18 A、CYP 3A 5 *3和MDR 1 C3435 T变异等位基因频率分别为0.005（95%可信区间（CI）0.048，0.0049）、0.783（95% CI 0.781，0.785）和0.528（95% CI 0.526，0.531），这些等位基因表现为不完全连锁不平衡。CYP 3A 5 *1/*1基因型受试者（n = 6）中环孢菌素剂量调整后的中位C-0为14.8 ng/mL/mg/kg（范围为11.1-26.8 ng/mL/mg/kg），在CYP 3A 5 *1/*3患者（n = 34）中，为23.7 ng/mL/mg/kg（范围9.0-61.0 ng/mL/mg/kg），CYP 3A 5 *3/*3患者（n = 66）为26.4 ng/mL/mg/kg（范围9.8-85.8 ng/mL/mg/kg; P = 0.012，克鲁斯卡尔-沃利斯检验）。因此，在肾移植后第一周，CYP 3A 5非表达者中环孢素剂量调整的C-0大于表达者。此外，与杂合子（n = 58）相比，MDR 1 C3435 T野生型纯合子（n = 21）的剂量校正C-0轻微但显著较低：17.7（10.3-60.8）对比26.4（9.0-67.3）ng/mL/mg/kg（P = 0.014，Mann-Whitney U-检验）。总之，本研究表明，CYP 3A 5的遗传多态性可能是部分原因，中国患者肾移植术后早期环孢素药代动力学的个体间差异较大。与携带CYP 3A 5 *1等位基因的患者相比，携带CYP 3A 5 *3变异基因型的患者需要低剂量的环孢霉素才能达到目标水平。
The calcineurin inhibitor cyclosporine is widely used to prevent allograft rejection after solid organ transplantation. It has a narrow therapeutic index and shows considerable interindividual differences in its pharmacokinetics. Interindividual differences in the activity and expression of the metabolising enzymes cytochrome P450 (CYP) 3A4 and 3A5 and the multidrug efflux pump P-glycoprotein (P-gp) contribute considerably to cyclosporine pharmacokinetics. Variability in the activity of CYP3A4, CYP3A5 and P-gp could be considered to result from genetic polymorphisms encoding their genes.The aim of the present study was to evaluate retrospectively the effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine dose adjusted trough blood concentration during the early period after renal transplantation in Chinese patients.One hundred and six renal transplant recipients in China were genotyped by polymerase chain reaction-restriction fragment length polymorphism for CYP3A4*18A, CYP3A5*3 and MDR1 C3435T. Cyclosporine whole blood levels were measured by fluorescence polarization immunoassay. Dose-adjusted trough blood concentrations (C-0) were determined and compared among the different genotype groups.The frequency of the CYP3A4*18A, CYP3A5*3 and MDR1 C3435T variant alleles were 0.005 (95% confidence interval (CI) 0.048, 0.0049), 0.783 (95% CI 0.781, 0.785) and 0.528 (95% CI 0.526, 0.531), respectively, and these alleles exhibited incomplete linkage disequilibrium. The median cyclosporine dose-adjusted C-0 in CYP3A5*1/*1 genotype subjects (n = 6) was 14.8 ng/mL per mg per kg (range 11.1-26.8 ng/mL per mg per kg), in CYP3A5*1/*3 patients (n = 34) it was 23.7 ng/mL per mg per kg (range 9.0-61.0 ng/mL per mg per kg) and for CYP3A5*3/*3 patients (n = 66) it was 26.4 ng/mL per mg per kg (range 9.8-85.8 ng/mL per mg per kg; P = 0.012, Kruskal-Wallis test). Accordingly, cyclosporine dose-adjusted C-0 was larger in CYP3A5 non-expressors than expressors in the first week after renal transplantation. In addition, wild-type homozygotes (n = 21) for MDR1 C3435T had a slight but significantly lower dose-adjusted C-0 compared with heterozygotes (n = 58): 17.7 (10.3-60.8) versus 26.4 (9.0-67.3) ng/mL per mg per kg, respectively (P = 0.014, Mann-Whitney U-test).In conclusion, the present study shows that genetic polymorphisms in CYP3A5 may be responsible, in part, for the large interindividual variability of cyclosporine pharmacokinetics during the early phase after renal transplantation in Chinese patients. Patients with the CYP3A5*3 variant genotype require a low dose of cyclosporine to reach target levels compared with those with the CYP3A5*1 allele.