Effects of Gene Polymorphism on the Increasing of Tacrolimus Blood Concentration Induced by Wuzhi Capsules in Renal Transplantation Patients / 中国药房

ABSTRACT

OBJECTIVE：To inve stigate the effects of polymorphism of CYP3A4，CYP3A5 and other genes on the increasing of tacrolimus blood concentration by Wuzhi capsules in renal transplantation patients. METHODS ：Totally 194 patients in Han nationality underwent renal transplantation and rece ived outpatient follow-up after surgery were selected from the First Affiliated Hospital of Anhui Medical University during Aug. 2015-Nov. 2018，and then divided into single drug group （107 cases）and combination group （87 cases）according to using of Wuzhi capsules or not. Single drug group was given Tacrolimus capsules 0.1-0.15 mg/kg，po，bid+Mycophenolate mofetil capsule s 0.5-0.75 g，bid or Mycophenolate sodium enteric-coated tablets 360-540 mg，bid+Prednisone acetate tablets 10 mg，qd；combination group was additionally given two Wuzhi capsules ，bid，on the basis of single drug group. Two groups were treated at least 7 d. The clinical data （such as patients ’sex and age ）were collected ，and enzyme amplification immunoassay was used to detect steady-state valley concentration of tacrolimus ，and calculate valley concentration/daily dose （C/D）value. PCR was adopted to detect patient genotyping of CYP3A5 gene rs 4646457，rs15524 and rs776746 locus，CYP3A4 gene rs 4646437，rs2242480 and rs 35599367 locus，ABCB1 gene rs 1128503 locus，ABCC2 gene rs3740066 locus，NR1I2 gene rs 3814055 locus，POR gene rs 1057868 locus，PPARA gene rs 4253728 locus，IL-3 gene rs 181781 locus， IL-10 gene rs 1800896 locus，CTLA4 gene rs 4553808 locus，CYP2C19 gene rs 4244285 and rs 4986893 locus，respectively. The correlation of each factor and tacrolimus C/D value was analyzed by Kruskal-Wallis test or Spearman rank test. Multivariate linear regression was conducted. RESULTS ：In 194 renal transplanation patients ，only wild type at rs 3599367 locus of CYP3A4 gene and rs4253728 locus of PPARA gene were detected ，and each genotype distribution of other genes was consistent with the Hardy-Weinberg equilibrium （P＞0.05）. Single factor analysis and multiple linear regression analysis showed that the combination of Wuzhi capsules and rs 776746 polymorphism of CYP3A5 gene were related to tacrolimus C/D value（P＜0.05）. There was statistical significance in tacrolimus C/D values among different genotypes of CYP3A5 gene in single drug group and combnation group（P＜0.05）. C/D value of GG and AG genotype in single drug group were significantly lower than combination group （P＜ 0.05），while there was no statistical significance in tacrolimus C/D value of AA genotype between 2 groups （P＞0.05）. CONCLUSIONS：Combination of Wuzhi capsules or not and polymorphism of CYP3A5 gene rs 776746 locus are associated with blood concentration of tacrolimus in renal transplantation patients in Han nationality. Combined use of Wuzhi capsules can increase blood concentration of tacrolimus in GG and AG genotype ，but have no significant effect on AA genotype.