尿甘二磷酸葡醛酸转移酶基因多态性对米格列奈在人体内药代动力学个体差异的影响

目的研究尿甘二磷酸葡醛酸转移酶UGT1A3和UGT2B7基因多态性对米格列奈在人体内药代动力学个体差异的影响,为临床制定合理的用药方案提供依据。方法选取12名健康志愿者,应用液质联用法分别检测单次和多次口服米格列奈的血药浓度,计算药代动力学参数,用焦磷酸测序法检测UGT1A3（rs：28898617;rs：3821242;rs：45625338;rs：6431625）和UGT2B7（rs：12233719;rs：7439366）SNP,并按不同基因型分组。结果米格列奈药代动力学个体差异很大。单次给药后米格列奈药代动力学参数（AUC、Cmax、CL）个体差异与UGT1A3和UGT2B7基因多态性间无显著性差异。多次给药后米格列奈药代动力学参数个体差异与UGT1A3基因多态性间相关性经方差分析得出PAUC〈0.05,且UGT1A3＊1/＊5：UGT1A3＊1/＊2：UGT1A3＊1/＊3=1.59：1.03：1,Pd=0.06（〉0.05）,但UGT1A3＊1/＊5组与UGT1A3＊1/＊2组的LSD-t检验两两比较Pq=0.032（〈0.05）,且UGT1A3＊1/＊5：UGT1A3＊1/＊2：UGT1A3＊1/＊3=1：1.57：1.59,表明它们代谢米格列奈的酶活性比较UGT1A3＊1/＊3〉UGT1A3＊1/＊2〉UGT1A3＊1/＊5。UGT2B7基因多态性与米格列奈药代动力学个体差异之间相关性在本试验中无显著性差异。结论尿苷二磷酸葡醛酸转移酶UGT1A3基因多态性对米格列奈体内药代动力学个体差异有影响;UGT2B7基因多态性与米格列奈体内药代动力学个体差异不存在相关性。

Effects of UGT Genetic Polymorphism on the Pharmacokinetics of Mitiglinide in Chinese Subjects

Objective To detect the effect of phase Ⅱ metabolic enzymes UGT1A3 and UGT2B7 genetic polymorphism on individuals＇ difference of mitiglinide pharmacokinetics in Han subjects,and to facilitate rational clinical use of the drug.Methods 12 healthy volunteers were selected,and high performance liquid chromatography-MS was used to detect their single and multiple oral mitiglinide blood concentration,then acquire the pharmacokinetic parameters respectively.Pyrosequencing was used to detect the UGT1A3 and UGT2B7 SNP.The subjects were grouped according to different genotypes.Results The drug showed great individual difference in pharmacokinetics,which was not related to UGT1A3 and UGT2B7 genetic polymorphism by statistical analysis for single oral mitiglinide,but was related to UGT1A3 genetic polymorphism for multiple oral mitiglinide.Conclusion Phase Ⅱ metabolic enzymes UGT1A3 gennetic polymorphism has impact on individual PK difference of mitiglinide,but UGT2B7 does not.