成人肾移植术后血糖控制和CYP3A5基因多态性对他克莫司谷浓度的影响  

Effects of glycaemic control and CYP3A5 polymorphisms on tacrolimus trough concentrations after adult kidney transplantation

作　　者：李坤 李璐璐 李楠楠 胡卫红 周建超[1] LI Kun;LI Lulu;LI Nannan;HU Weihong;ZHOU Jianchao(Department of Pharmacy,The Third Affiliated Hospital Of Zhengzhou University,Zhengzhou 450052,Henan,China;Department of Obstetrical,The Third Affiliated Hospital Of Zhengzhou University,Zhengzhou 450052,Henan,China)

机构地区：[1]郑州大学第三附属医院药学部,河南郑州450052 [2]郑州大学第三附属医院产科,河南郑州450052

出　　处：《中国临床药理学与治疗学》2023年第7期767-774,共8页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：河南省医学科技攻关计划项项目(LHGJ20190406)。

摘　　要：目的:糖尿病影响细胞色素P4503A4/5(CYP3A4/5)底物的药代动力学。因此本研究评估了血红蛋白A1c(HbA1c)水平与他克莫司的药代动力学之间的关系。方法:回顾性收集肾移植术后口服他克莫司的患者,年龄>18岁。CYP3A5基因型分为表达者(^(*)1/^(*)1或^(*)1/^(*)3)和非表达者(^(*)3/^(*)3)。多元线性回归分析确定服用他克莫司后第7天、6个月和12个月的谷浓度/剂量标准化体质量(C/D)比值的预测因子。使用Bonferroni校正评估服用他克莫司后6个月和12个月时ΔC/D比值与ΔHbA1c水平之间的相关性。结果:根据入排标准纳入139名患者(CYP3A5表达者,n=56和非表达者,n=83),多元线性回归分析显示CYP3A5非表达者第7天的C/D比值略高于CYP3A5表达者。治疗6个月和12个月后影响他克莫司C/D比值升高的因素分别是男性和CYP3A5非表达者以及HbA1c水平升高和CYP3A5非表达者。在CYP3A5非表达患者中12个月后他克莫司C/D比值和HbA1c水平中呈正相关(y=54.6x-194.6,R=0.63,P=0.004,Bonferroni校正)。此外,从6个月到12个月,C/D比值和HbA1c水平的个体内变化有相关趋势(y=54.5x+20.2,R=0.41,P=0.036,Bonferroni校正)。结论:可以考虑使用HbA1c和CYP3A5基因型来了解肾移植6个月后他克莫司浓度的个体间和个体内变异性。AIM:Diabetes mellitus affects the pharmacokinetics of cytochrome P4503A4/5(CYP3A4/5)substrates.We evaluated the relationship between haemoglobin A1c(HbA1c)levels and the pharmacokinetics of controlled-release tacrolimus.METHODS:This retrospective observational cohort study included kidney transplant recipients(>18 years)receiving controlled-release tacrolimus orally.CYP3A5 genotypes were categorized as expressers(^(*)1/^(*)1 or^(*)1/^(*)3)and non-expressers(^(*)3/^(*)3).Multiple linear regression analysis determined the predictors for trough concentration/dose-normalized by body weight(C/D)ratio of tacrolimus at 7 days,6 months and 12 months after administration.Correlations between the C/D ratio and HbA1c levels at baseline,6 and 12 months after tacrolimus initiation were evaluated with Bonferroni correction.RESULTS:Out of 42 patients(CYP3A5 expressers,n=56,and non-expressers,n=83),the multiple linear regression analysis showed that the C/D ratio on Day 7 was marginally higher in CYP3A5 non-expressers than in CYP3A5 expressers.Factors affecting the elevation of tacrolimus C/D ratio after 6 and 12 months of treatment were male sex and CYP3A5 non-expressers and increased HbA1c levels and CYP3A5 non-expressers,respectively.The C/D ratio and HbA1c levels after 12 months was positively correlated in CYP3A5 nonexpressers(y=54.6x+194.6,R=0.63,P=0.004,Bonferroni correction).Furthermore,intra-individual changes in the C/D ratio and HbA1c levels from 6 to 12 months were nearly correlated(y=54.5x+20.2,R=0.41,P=0.036,Bonferroni correction).CONCLUSION:HbA1c and CYP3A5 genotypes might be considered to understand the inter-and intra-individual variability in blood tacrolimus concentrations after 6 months post-kidney transplantation.

关 键 词：糖尿病 药物基因组学 药物代谢动力学 他克莫司 肾移植 

分 类 号：R969[医药卫生—药理学]