中国肾移植患者红细胞内嘌呤类药物活性代谢物6-硫鸟嘌呤核苷酸浓度监测及影响因素分析

Analysis of thiopurines active metabolite 6-thioguanine nucleotide monitoring in erythrocytes and influencing factors in Chinese renal transplant recipients

目的:研究服用硫唑嘌呤(AZA)中国肾移植患者红细胞(RBC)内活性代谢物6-硫鸟嘌呤核苷酸(6-TGNs)分布特征及影响因素,为临床合理应用嘌呤类药物提供依据。方法:以89例中国肾移植患者为研究对象,关联分析年龄、性别、体质量、AZA剂量和TPMT活性对RBC内6-TGNs浓度的影响,并应用SPSS v20.0软件进行多元线性回归分析。结果:89例中国肾移植患者RBC内6-TGNs浓度呈非正态分布(P<0.000 1),6-TGNs浓度中位数为167.60(四分位间距,108.10~300.80)pmol/8×10~8 RBC,个体间差异约24.3倍。关联分析显示患者年龄、性别、体质量、TPMT活性对6-TGNs浓度均无显著影响(P>0.05);而AZA剂量与6-TGNs浓度间呈显著正相关性(rs=0.307 1,P<0.01)。多元线性回归分析显示,RBC内6-TGNs浓度与AZA剂量间呈显著正相关(P<0.001),与TPMT活性呈显著负相关(P<0.05)。结论:AZA剂量和RBC内TPMT活性协同影响嘌呤类药物活性代谢物6-TGNs浓度,进而影响该类药物临床疗效和毒性反应。

OBJECTIVE To investigate the distribution characteristics and influencing factors of thiopurines active metabolite 6-thioguanine nucleotide(6-TGNs) in human red blood cell(RBC) in Chinese renal transplant recipients who were treated with azathiopurine(AZA), and to provide references for the clinical use of thiopurines. METHODS A total of 89 Chinese renal transplant recipients were enrolled as the subjects. The effects of age, gender, weight, AZA dose and TPMT activity on the 6-TGNs concentration in human RBC were statistically analyzed, and multivariate linear regression analysis was performed using SPSS v20.0 statistical software. RESULTS The concentration of 6-TGNs in RBCs of 89 Chinese renal transplant patients was not normally distributed(P<0.001), and the median concentration of 6-TGNs was 167.60[interquartile range(IQR), 108.10~300.80] pmol/8×10~8 RBC with an inter-individual variation of about 24.3-fold. Correlation analysis showed that patient age, gender, body weight, and TPMT activity had no significant effect on the concentration of 6-TGNs(P>0.05);however, there was a significant positive correlation between AZA dose and the concentration of 6-TGNs(rs=0.307 1, P<0.01). Multivariate linear regression analysis showed a significant positive correlation between 6-TGNs concentration in RBC and AZA dose(P<0.001) and a significant negative correlation with TPMT activity(P<0.05).CONCLUSION The dose of AZA and the activity of TPMT in RBC affect the concentration of 6-TGNs, the active metabolite of purine drugs, thereby affecting the clinical efficacy and toxicity of these drugs.