Objective: To determine the effect of genetic polymorphisms of the metabolic enzyme UGT on individual differences of mitiglinide pharmacokinetic (PK) in Chinese, and provide a basis for the clinical rational usage of the drug. Methods; Health volunteers took single and multiple oral doses of mitiglinide. HPLC-MS was used to detect blood concentration of mitiglinide, pyrosequencing was used to detect the SNPs of UGT1A3 and UGT2B7. Then, the pharmacokinetic parameters were acquired respectively, and the volunteers were divided into groups according to the different genotypes. The PK parameters between groups (or among groups) were compared using ANOVA or two independent-samples t test; P UGT1 A3 * 1/ * 3 > UGT1A3 * 1/ * 1 > UGT1 A3 * 1/ * 2 > UGT1 A3 * 1/ * 5, and the genetic polymorphism of UGT2B7-1 was T/T > G/T>G/G. Conclusion: The genetic polymorphisms of phase II metabolic enzymes, UGT1A3 and UGT2B7-1 but not UGT2B7-2, impact individual PK difference of mitiglinide.%目的:研究尿苷二磷酸葡萄糖醛酸转移酶(uridine-5'-diphosphate glucuronosyl transferase,UGTs)基因多态性对米格列奈在中国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:健康受试者单次和多次给药米格列奈片,测定其血药浓度并计算药代动力学参数,同时检测分析UGTlA3和UGT2B7基因多态性.按不同基因型分组,组间药代动力学参数的比较应用单因素方差分析和二独立样本t检验,组间多重差异比较采用LSD-t检验.结果:单次给药后米格列奈药代动力学参数个体差异与UGTlA3和UGT2B7基因多态性间相关性经方差分析和独立样本t检验P＞0.05,不存在相关性;多次给药后米格列奈的药代动力学参数个体差异与UGTlA3基因多态性间相关性经方差分析,FAUC=11.279,PAUC=0.001,FCL=16.712,PCL=0.001,差异显著,表明UGT1A3代谢米格列奈的酶活性为UGT1A3*2/*4＞UGT1A3*1/*3＞UGT1A 3*1/*1＞UGT1A3*1/*2＞UGT1A3*1/*5;多次给药UGT2B7-1的药代动力学参数FAUC=3.980,PAUC=0.027,FCL=4.433,PCL=0.018,差异显著,表明UGT2B7-1基因代谢米格列奈的酶活性为T/T＞G/T＞G/G.单次或多次给药,UGT2B7-2基因型与米格列奈药代动力学个体差异间无相关性(P均＞0.05).结论:UGTlA3和UGT2B7-1基因多态性对米格列奈体内代谢动力学个体差异有显著影响;UGT2B7-2基因多态性与米格列奈体内代谢动力学个体差异间不存在相关性.
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