CYP3A5*3基因多态性与他克莫司血药浓度及临床疗效的相关性研究

目的 探讨CYP3A5*3在中国人群中的分布,明确其对他克莫司稳态谷浓度的影响及临床疗效的相关性。 方法 收集55例慢性肾小球肾炎患者的他克莫司稳态谷浓度,酶免疫放大分析法测定其浓度值,根据TL998A荧光检测仪及试剂盒要求进行样品处理及CYP3A5*3基因型测定。分析CYP3A5*3不同基因型对他克莫司血药浓度及临床疗效的影响。 结果 55例患者,共收集他克莫司稳态谷浓度268份, 5~<10 ng.mL_^-1 与10~20 ng.mL_^-1浓度范围他克莫司的临床有效率(82.0%,82.6%)显著高于5 ng.mL_^-1以下浓度范围(45.5%)(p<0.05),同时5~<10 ng.mL_^-1 与10~20μg.mL_^-1浓度范围他克莫司的临床有效率相近(p＞0.05)。CYP3A5*3三种基因型(GA、GG、AA)患者分布频率均符合Hardy－Weinberg平衡(p＞0.05)。三种基因型患者他克莫司血药谷浓度比较,差异无统计学意义(p＞ 0.05)；他克莫司剂量和C/D值比较,差异均有统计学意义(p<0.05)。其中突变纯合子GG患者的他克莫司剂量显著低于突变杂合子GA和野生型AA患者,且突变杂合子GA患者显著低于野生型AA患者；突变纯合子GG患者的他克莫司C/D显著高于突变杂合子GA和野生型AA患者,且突变杂合子GA患者显著高于野生型AA患者。C3435T 基因型不同的患者临床有效率相近(p＞ 0.05)。 结论CYP3A5*3基因多态性对我国肾小球肾炎患者他克莫司血药浓度有显著影响,等位基因G携带者他克莫司C/D值更高,且每日所需剂量更低；但CYP3A5*3基因多态性可能与临床疗效无关。

Study on Correlation of CYP3A5*3 Gene Polymorphisms with Tacrolimus Blood Drug Level and Clinical Efficacy

OBJECTIVE To investigate the distribution of CYP3A5*3 in Chinese population, and clarify its correlation with blood drug level and clinical efficacy of tacrolimus. METHODS Two hundred and sixty-eight tacrolimus steady state minimal concentration samples were collected from 55 patients with chronic glomerulonephritis. The blood drug level of tacrolimus was measured by enzyme multiplied immunoassay technique. The genotypes of CYP3A5*3 were determined by TL998A fluorescence detector. The association between different CYP3A5*3 genotypes and the blood drug level and clinical efficacy of tacrolimus were analyzed. RESULTS In 268 parts of tacrolimus steady state minimal concentration, the curative effect of 5-< 10 ng·mL^-1(82.0%) and 10-20 ng·mL^-1(82.6%) were significantly higher than that of <5 ng·mL^-1(P<0.05). And the clinical efficiency of tacrolimus in the range of 5-<10 ng·mL^-1 and 10-20 ng·mL^-1 were similar. Use the pairwise comparison methods to compare steady state minimal concentration, daily dose, minimal concentration/daily dose(C/D) showed that the steady state minimal concentration of tacrolimus with GA and GG genotype patients were significantly increased than that of AA genotypes, and GA genotype recipients were higher than that of GG genotypes(P<0.05). Tacrolimus dose of GG genotype patients were significantly lower than those of GA and AA genotypes, and GA genotype patients were lower than that of AA genotypes (P<0.05). C/D value of GG genotype patients were significantly higher than those of GA and AA genotypes, and GA genotype recipients were higher than that of AA genotypes(P<0.05). However, the clinical efficacy of tacrolimus with mutant type and wild type of CYP3A5*3 were similar. CONCLUSION CYP3A5*3 genetic polymorphism significantly influences tacrolimus concentration in Chinese chronic glomerulonephritis patients, and G allele carriers have higher C/D values and need smaller tacrolimus daily dose. CYP3A5*3 genetic polymorphism may be not associated with clinical efficacy.