基因多态性对先天性心脏病儿童舒芬太尼药代动力学的影响  

Effects of Gene Polymorphism on the Pharmacokinetics of Sufentanil in Children with Congenital Heart Disease

作　　者：李碧莲 王思怡 白雪[1] 刘瑶 魏伟[1] 管宴萍 钟国平[2] 宋兴荣[1] LI Bi-lian;WANG Si-yi;BAI Xue;LIU Yao;WEI Wei;GUAN Yan-ping;ZHONG Guo-ping;SONG Xing-rong(Department of Anesthesiology,Guangzhou Women and Children's Medical Center,Guangzhou Medical University,Guangzhou 510120,China;Institute of Clinical Pharmacology,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510080,China)

机构地区：[1]广州医科大学广州市妇女儿童医疗中心麻醉科,广东广州510120 [2]中山大学药学院临床药理研究所,广东广州510180

出　　处：《中山大学学报（医学科学版）》2022年第1期124-132,共9页Journal of Sun Yat-Sen University:Medical Sciences

基　　金：国家自然科学基金(81901385);广州市妇女儿童医疗中心/广州市儿科研究所基金(IP-2019-011)。

摘　　要：【目的】探讨基因多态性对先天性心脏病儿童心脏介入手术中舒芬太尼(SUF)药代动力学的影响。【方法】选择年龄6~72月,ASA分级Ⅱ级并拟行心脏介入手术的患儿168例。使用丙泊酚2 mg·kg^(-1)、SUF 0.3μg·kg^(-1)及苯磺顺阿曲库铵0.2 mg·kg^(-1)行麻醉诱导,丙泊酚8 mg·kg^(-1)·h^(-1)维持麻醉。采用稀释采样法收集给予SUF后5、10、20、30、45、60、75、90 min的血液标本。使用UHPLC-MS/MS法测定血浆中SUF的药物浓度,并用Phoenix Win Non⁃lin^(TM)软件计算药代动力学参数。基因型检测采用基质辅助激光解析电离飞行时间质谱进行检测。应用SNPStats对基因型数据和药代动力学数据进行分析,选择赤池信息量准则数值最小的模型为最优模型。【结果】共纳入可能影响SUF药代动力学和药效学相关的靶点、代谢酶、转运体及通路相关的9个基因中30个单核苷酸多态性位点。发现基因ABCG2 rs2054576和OPRM1 rs4870266与SUF药物暴露量相关(P<0.05);OPRM1 rs2236257与SUF表观分布容积相关(P<0.05);CYP3A4 rs2246709和OPRM1 rs2236257,rs4870266与SUF药物清除率相关(P<0.05)。【结论】在儿童先天性心脏病介入手术中,ABCG2 rs2054576,CYP3A4 rs2246709和OPRM1 rs2236257,rs4870266的基因多态性可显著地影响SUF的药代动力学变化。【Objective】To investigate the effects of gene polymorphism on the pharmacokinetics of sufentanil(SUF)in children with congenital heart disease undergoing interventional cardiac surgery.【Methods】A total of 168 ASA gradeⅡpatients aged 6~72 months and scheduled for interventional cardiac surgery were enrolled into the study.Anesthesia was induced by using propofol 2 mg·kg^(-1),SUF 0.3μg·kg^(-1)and cisatracurium besilate 0.2 mg·kg^(-1).Propofol 8 mg·kg^(-1)·h^(-1)was administered to maintain anesthesia.Blood samples were collected at 5,10,20,30,45,60,75,90 min after administration of SUF by dilution sampling method.Plasma concentration of sufentanil was determined by UHPLC-MS/MS method and pharmacokinetic parameters were calculated by Phoenix Winnonlintm^(TM) software.The genotypes were detected by matrix-assisted laser desorption ionization-time of flight mass spectrometry(MALDI-TOF MS).The genotypes and pharmacokinetic data were analyzed by SNPStats software and the model with the smallest value of Akaike information criterion was chosen as the best model.【Results】Thirty single nucleotide polymorphisms(SNPs)in 9 genes possibly involved in pharmacokinetics,pharmacodynamics related targets,metabolic enzymes,transporters and pathways of SUF were examined.ABCG2 rs2054576 and OPRM1 rs4870266 were found to be related to area under the curve(AUC)(P<0.05).OPRM1 rs2236257 was correlated with the apparent volume of distribution(Vd)(P<0.05).CYP3A4 rs2246709,OPRM1 rs2236257 and rs4870266 were associated with the drug clearance rate(CL)(P<0.05).【Conclusion】Gene polymorphisms of ABCG2 rs2054576,CYP3A4 rs2246709 and OPRM1 rs2236257,rs4870266 could significantly affect the pharmacokinetics of SUF in children undergoing interventional cardiac surgery.

关 键 词：基因多态性 舒芬太尼 小儿 药代动力学 

分 类 号：R969.2[医药卫生—药理学]