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

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

关键词:  他克莫司  基因多态性  血药浓度  CYP3A5*3  慢性肾小球肾炎

Key words:  tacrolimus  gene polymorphisms  blood contentration  CYP3A5*3  chronic glomerulonephritis

摘要:

目的 探讨CYP3A5*3在中国人群中的分布，明确其与他克莫司稳态谷浓度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268份他克莫司稳态谷浓度，酶免疫扩大分析法测定其浓度值，采用TL998A荧光检测仪进行CYP3A5*3基因型测定。分析CYP3A5*3不同基因型对他克莫司谷浓度及临床疗效的影响。结果 268份他克莫司稳态谷浓度中，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（45.5%）（P<0.05），同时5~<10 ng·mL^-1与10~20 μg·mL^-1浓度范围他克莫司的临床有效率相近。CYP3A5*3各基因型（GA、GG、AA）患者他克莫司在血药谷浓度、日剂量和谷浓度/剂量（C/D）值两两比较结果显示：突变杂合子GA型和突变纯合子GG型患者血药谷浓度高于野生型AA型患者，且突变杂合子GA患者高于突变纯合子GG患者（P<0.05）；突变纯合子GG患者的他克莫司日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（P<0.05）；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（P<0.05）。CYP3A5*3基因型不同的患者临床有效率相近。结论 CYP3A5*3基因多态性对中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。

Abstract:

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.