CYP3A5^＊3和CYP3A4^＊18B基因多态性对肾移植患者环孢素药代动力学的影响

Effect of CYP3A5^＊3 and CYP3A4^＊18B genetic polymorphisms on cyclosporine pharmacokinetics in renal transplant patients

目的回顾性研究肾脏移植后1mon,CYP3A5*3和CYP3A4*18B基因多态性对CsA药代动力学参数的影响。方法采用PCR-RFLP方法分析了63名肾脏移植患者CYP3A5*3和CYP3A4*18B基因型;荧光偏正免疫法用于检测肾移植患者静脉全血中的CsA浓度。结果在63名肾移植患者中,CYP3A5*3和CYP3A4*18B突变等位基因发生频率分别为0.770(95CI:0.767～0.773),0.235(95CI:0.235～0.241),而且这些等位基因表现出完全连锁不平衡。在移植术后1mon内,携带CYP3A4*1/*1野生型纯合子患者的C0以及剂量校正谷血浓度(C0/D)均明显高于携带CYP3A4*1/*18B杂合子或CYP3A4*18B/*18B突变型纯合子患者(P<0.05,Mann-WhitneyUtest);CYP3A5*1/*1基因型组的给药剂量明显高于CYP3A5*1/*3或CYP3A5*3/*3基因型组(P=0.004<0.01,Kruakal-Wallistest);CYP34*18B和CYP3A5*3联合考虑,对于CYP3A5表达组,同样发现C0、C0/D在CYP3A4*1/*1组C0以及C0/D均明显高于CYP3A4*1/*18B或CYP3A4*18B/*18B组(P<0.05,Mann-WhitneyUtest);而其他药动学参数在CYP3A5*3及CYP3A4*18B各组间相比差异则没有统计学意义。结论CYP3A5*3和(或)CYP3A4*18B基因多态性对肾移植后1monCsA药代动力学有一定影响,移植前CYP3A5*3基因型的分析仍需进一步研究。

Aim To evaluate retrospectively the effect of genetic polymorphisms in CYP3A4 and CYP3A5 on cyelosporine pharmacokinetics during the early period in renal transplant patients. Methods Polymerase chain reaction-restriction fragment length polymorphism was performed to genotype for CYP3A4^＊ 18B and CYP3A5^＊ 3. Cyclosporine whole blood levels were measured by fluorescence polarization immunoassay. Results The frequencies of CYP3A4^＊ 18B and CYP3A5^＊3 variant alleles were 0. 235 （95 CI：0. 235 0. 241 ） and 0. 770 （95 CI ： 0. 767 - 0. 773 ）, respectively in 63 of renal transplantation patients, and these alleles exhibited incomplete linkage disequilibrium. The median （range） value of cyelosporine dose adjusted blood trough concentrations （C0/D） and CO in CYP3A4^＊ 1/^＊ 1 genotype patients was higher than that in CYP3A4^＊ 1/^＊ 18B and CYP3A^＊ 18B/^＊ 18B patients, the same result was found in CYP3A5 expression （CYP3A5^＊3/^＊1 and CYP3A5^＊ 1/^＊ 3） （P 〈 0.05, Mann-Whitney U test）; cyclosporine dose in CYP3A5^＊ 1/^＊ 1 genotype patients were higher than that in CYP3A5^＊ 1/^＊3 or CYP3A5^＊ 3/^＊ 3 patients （ P =0. 004 〈0.01, Kruakal-Wallis Test） in the first month after renal transplantation. In addition, no other statistically significant association was found between eyelosporine and CYP3A4^＊ 18B as well as CYP3A5^＊ 3 SNPs. Conclusions Genetic polymorphism of CYP3A5^＊ 3 and CYP3A4^＊ 18B may be partly responsible in large interindividual variability of cyclosporine pharmacokinetics after transplantation, but the test for CYP3A5^＊3 genotype before transplantation remains to be explained.