硫唑嘌呤药物代谢酶和转运体单核苷酸多态性对6-硫鸟嘌呤核苷酸稳态血药浓度和白细胞水平的影响  

Effects of single nucleotide polymorphisms of genes involved in transportation and metabolism of azathioprine on steady-state of 6-thioguanine nucleotide concentration and leukocyte levels

作　　者：王美伦 王珊珊[2] 汪燕燕[2] 张培培 夏泉[2] 李琳琳 宋帅 WANG Meilun;WANG Shanshan;WANG Yanyan;ZHANG Peipei;XIA Quan;LI Linlin;SONG Shuai(School of Pharmacy,Anhui University of Chinese Medicine,Anhui Hefei 230012,China;Department of Pharmacy,the First Affiliated Hospital of Anhui Medical University,Anhui Hefei 230012,China;Department of Gastroenterology,the First Affiliated Hospital of Anhui Medical University,Anhui Hefei 230012,China)

机构地区：[1]安徽中医药大学药学院,安徽合肥230012 [2]安徽医科大学第一附属医院药剂科,安徽合肥230022 [3]安徽医科大学第一附属医院消化内科,安徽合肥230022

出　　处：《中国医院药学杂志》2024年第23期2772-2778,共7页Chinese Journal of Hospital Pharmacy

基　　金：安徽高校自然科学研究项目(编号:2022AH051154);安徽省“十三五”临床重点专科建设项目(编号:卫科教秘[2017]529号);2022年安徽省大学生创新创业训练计划项目(编号:S202210366113);安徽省高校协同创新项目(编号:GXXT-2021-068)。

摘　　要：目的:探索硫唑嘌呤药物代谢酶和转运体单核苷酸多态性与克罗恩病患者6-硫鸟嘌呤核苷酸(6-TGNs)及其白细胞水平的相关性。方法:选取在安徽医科大学第一附属医院接受硫唑嘌呤治疗3个月以上的74名汉族患者为研究对象。采用HPLC法测定患者红细胞中6-TGNs的稳态谷浓度,基质辅助激光解吸电离飞行时间质谱检测患者TPMT rs1142345等22个位点的多态性。通过单因素和多重线性回归分析基因型、6-TGNs浓度和白细胞水平的相关性。结果:6-TGNs稳态谷浓度与白细胞和淋巴细胞水平呈负相关。单因素及多因素回归分析表明,6-TGNs绝对或相对浓度的增加与TPMT rs1142345、IPTA rs1127354突变有关。未发现NUDT15 rs116855232突变与6-TGNs和白细胞水平的相关性,而CT型患者中位标准剂量较野生型(CC)明显偏低(P<0.05)。ATIC rs3821353突变是预测患者服用硫唑嘌呤导致淋巴细胞减少的独立危险因素。结论:克罗恩病患者服用硫唑嘌呤前检测TPMT rs1142345、ITPA rs1127354、ATIC rs3821353和NUDT15 rs116855232基因型,用药期间密切监测6-TGNs和白细胞水平,有助于降低硫唑嘌呤引起的白细胞减少风险,提升临床治疗效果。OBJECTIVE To explore the relationship between polymorphisms of azathioprine metabolizing enzymes and transporters and the levels of 6-thioguanine nucleotides(6-TGNs)and leukocytes in patients of Crohn's disease(CD).METHODS A total of 74 Han patients on a treatment of azathioprine for over 3 months at First Affiliated Hospital of Anhui Medical University were recruited.The steady-state trough concentration of 6-TGNs in red blood cells was measured by high performance liquid chromatography(HPLC).Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was utilized for detecting 22 loci of single nucleotide polymorphisms,including TPMT rs1142345.The correlations between genotypes,concentration of 6-TGNs and levels of white blood cells were examined by univariate and multiple linear regression analyses.RESULTS The results of univariate and multivariate regression analyses revealed that the elevations in absolute or relative concentrations of 6-TGNs were associated with mutants of TPMT rs1142345 and ITPA rs1127354.No correlation existed between NUDT15 rs116855232 mutation and the levels of 6-TGNs and white blood cells.However,patients of CT genotype had significantly lower median standard doses as compared with those with wild-type(CC)genotype(P<0.05).ATIC rs3821353 mutation served as an independent risk factor for predicting lymphocyte reduction in patients on a treatment of azathioprine.CONCLUSION Detecting TPMT rs1142345,ITPA rs1127354,ATIC rs3821353,NUDT15 rs116855232 genotypes,as well as 6-TGNs and leukocyte levels in CD patients before and after azathioprine dosing are vital in lowering the risk of azathioprineinduced leukopenia and improving therapeutic efficacy.

关 键 词：治疗药物监测 克罗恩病 6-硫鸟嘌呤核苷酸 硫唑嘌呤 单核苷酸多态性 

分 类 号：R969[医药卫生—药理学]