CYP3A5基因多态性对膜性肾病患者他克莫司初始剂量的预测价值

Prediction of initial dosage of tacrolimus in patients with idiopathic membranous nephropathy by testing CYP3A5 genetic polymorphisms

目的检测不同CYP3A5基因型的特发性膜性肾病患者应用他克莫司（TAC）后达到目标血药物浓度时的用药剂量，明确不同基因型与药物用量间的关系，初步探索TAC的最佳初始用药剂量。方法采用回顾性分析的方法，病例来自滨州医学院附属医院肾内科确诊的特发性膜性肾病患者60例，荧光染色原位杂交（FISH）法检测CYP3A5基因型。依据基因型将患者分为AA、AG、GG3组。均相酶扩大免疫分析法（EMIT）测定患者他克莫司的全血谷浓度（C0）；比较3组患者用药后8、12、16、24周时他克奠司全血谷浓度（C0）、用药剂量、全血谷浓度与用药剂量（C0／D）的比值。按照临床疗效分为完全缓解（CR）、部分缓解（PR）和无效（NR）3组，比较各访视点患者的TAC药代动力学指标。结果60例特发性膜性肾病患者CYP3A5基因多态性（A6986G）G的基因频率为53．33％，其中AA组12例（20％）；AG组32例（53．33％）；GG组16例（26．67％）。3组患者他克莫司用药8、12、16、24周后的用药剂量、全血谷浓度／用药剂量比值的差异有统计学意义（均P〈0．05）。AA组患者他克莫司用药剂量约为GG组的2～3倍，AG组约为GG组的1～2倍。治疗24周AA组患者的缓解率显著低于AG、GG组（16．67％比81．25％、16．67比87．25％，均P〈0．001）。CR、PR组的C0以及C0/D值均较NR组高，且随用药时间延长而升高，但组间差异无统计学意义（P〉0．05）。结论CYP3A5基因多态性与他克莫司血药浓度明显相关，CYP3A5基因型检测对指导特发性膜性肾病患者的个体化用药有一定临床实用价值。

Objective To explore the effect of CYP3A5 gene polymorphisms on the whole blood trough concentration （Co） of taerolimus （TAC） in patients with idiopathic membranous nephropathy to identify an economical and optimal initial dosage delivering the best curative effect with minimum drug adverse reaction. Methods Sixty patients with idiopathic membranous nephropathy were enrolled in this study. The CYP3A5 genotype was tested by fluorescence in situ hybridization （FISH）. According to CYP3A5 genotype, the patients were divided into three groups （AA, AG, and GG）. At the same time, the Co of TAC was measured by enzyme multiplied immunoassay technique （EMIT）. Co of TAC, daily dosage of TAC and the concentration/dose（C0/D） ratio of TAC were detected after taking medicine at 8, 12, 16 and 24 weeks respectively, so as to corroborate the relation between CYP3A5 gene polymorphisms and the dosage of TAC. Results The oral TAC dosage had great variation among individuals. The occurrence of the CYP3A5 genetic polymorphisms （A6986G） designated as G was 53.33%. D and Co were significantly different at 8, 12, 16 and 24 weeks respectively （all P 〈 0.05）. To reach the same Co, the patients with AA needed 2-3-fold dosage of TAC than GG; and those with AG needed 1-2-fold dosage of TAC than GG. After 24-week treatment, the effective rate of AA group was markedly lower than AG and GG （16.67% vs 81.25%, 16.67% vs 87.50%, all P 〈 0.001）. Among CR, PR and NR, there were no significantly difference on Co or C0/D of TAC （P 〉 0.05）. Conclusions CYP3A5 genotypes are correlated with blood concentration of TAC. CYP3A5 genotyping may be a new approach to predict the optimal initial dosage of tacrolimus in idiopathic membranous nephropathy.