关键词: 肝移植, 他克莫司, 谷浓度, 新发糖尿病, 细胞色素P450家族成员3A5

Abstract: AIM: To analyze the influence of donor and recipient CYP3A5 genotype on tacrolimus trough concentrations in the early stage after liver transplantation and its clinical significance under therapeutic drug monitoring (TDM) strategy retrospectively.  METHODS: A total of 125 patients undergoing liver transplantation in Shanghai General Hospital from January 2015 to March 2019 were involved in this study. Clinical pharmacology parameters and liver function indexes from 1 to 28 days after operation, the occurrence of new onset diabetes mellitus (NODM) was collected. Donor and recipient cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) gene rs776746 locus were genotyped by RT-PCR technology.RESULTS: Median trough concentration (Ctmed) and maximum trough concentration (Ctmax)of tacrolimus in the first week after liver transplantation were (8.3±7.0) ng/mL, (11.2±12.9) ng/mL, respectively. Patients were divided 4 subgroups according to CYPA35 rs776746 genotype: recipients with AA/AG genotype carrying AA/AG genotype donor, recipients with AA/AG genotype carrying GG genotype donor, recipients with GG genotype carrying AA/AG genotype donor and recipients with GG genotype carrying GG genotype donor. There was significant difference of Ctmed and Ctmax in each subgroup (P<0.01). ROC curve analysis showed that the AUC of tacrolimus Ctmax in predicting NODM was 0.716 8 (P=0.000 5) and optimal diagnostic threshold concentration was 14.4 ng/mL. Ct med couldn't predict NODM (P=0.193 6). Preoperative blood glucose level (OR: 5.076, P=0.043), preoperative total cholesterol level (OR: 3.752, P=0.022), glucocorticoid therapy after operation (OR: 12.846, P=0.015) and tacrolimus Ctmax (OR: 17.796, P=0.014) were independent risk factors of NODM. Donor and recipient CYP3A5 genotype had a marked impact on Ctmax. The proportion of patients with Ctmax greater than or equal to 14.4 ng/mL in each subgroup were 14.70%(5/34), 33.33%(12/36), 61.11%(11/18) and 78.57 (22/28), there were significant differences among the four groups (P<0.000 1). CONCLUSION: To combine TDM strategy and donor and recipient CYP3A5 genotype will be helpful to guide tacrolimus administration and reduce the incidence of NODM in liver transplantation.

Key words: liver transplantation, tacrolimus, trough concentrations, new onset diabetes mellitus, cytochrome P450, family 3, subfamily A, polypeptide 5