OCT1基因rs2282143 rs628031和rs36056065多态性对二甲双胍药代动力学的影响

Effects of OCT1 gene rs2282143,rs628031 and rs36056065 polymorphism on metformin pharmacokinetics in healthy subjects

目的探讨有机阳离子转运体1(OCT1)基因中rs2282143(P341L,1022C>T)、rs628031(M408V,1222A>G)和rs36056065(ins/del GTAAGTTG)多态性对二甲双胍药代动力学的影响。方法 65例男性健康自愿者空腹口服盐酸二甲双胍片500mg,采用液相色谱-串联质谱法测定血浆中二甲双胍的浓度,并根据rs2282143、rs628031和rs36056065多态性进行分组。结果 rs2282143多态性中CC、CT和TT分别为45例(69.2%)、19例(29.2%)和1例(1.5%),CC和CT组间的Cmax、Tmax、AUC0-t、AUC0-∞和T1/2差异无统计学意义(P>0.05)。rs628031与rs36056065等位基因完全连锁,其中AA/ins、AG/ins-del和GG/del分别为8例(12.3%)、24例(36.9%)和33例(50.8%)。AG/ins-del的Cmax、AUC0-t、AUC0-∞显著高于AA/ins和GG/del,差异有统计学意义(P<0.05),AA/ins和GG/del之间差异无统计学意义(P>0.05);Tmax、T1/2在3种基因型间差异无统计学意义(P>0.05)。结论 rs2282143多态性与二甲双胍药代动力学无相关性,完全连锁的rs628031和rs36056065与二甲双胍药代动力学密切相关。

Objective To explore the effects of organic cation transporter 1（OCT1） gene rs2282143（P341L , 1022C〉 T） ,rs628031（M408V ,1222A〉 G） and rs36056065（ins/del GTAAGTTG） polymorphisms on metformin pharmacokinetics in healthy volunteers .Methods 65 healthy men were given a single oral dose of 500 mg metformin , and the plasma concentrations of metformin were measured for up to 24 h by LC-MS/MS .The subjects were divided into different groups according to polymorphisms of rs2282143 ,rs628031 and rs36056065 .Results The allele CC ,CT and TT of the rs2282143 were 45（69 .2% ） ,19（29 .2% ） and 1（1 .5% ） in 65 subjects ,respectively .There was no difference of Cmax ,Tmax ,AUC0-t ,AUC0-∞ and T1/2 between CC and CT in the rs2282143 .The polymorphisms rs628031 and rs36056065 were completely linkage disequilibrium and the presence of allele AA/ins、AG/ins-del and GG/del were 8（12 .3% ） ,24（36 .9% ） and 33（50 .8% ） in our subjects ,respectively .The Cmax ,AUC0-t ,AUC0-∞ of allele AG/ins-del were significantly higher than the allele AA/ins and GG/del ,whereas no difference was observed between the allele AA/ins and GG/del ,respectively （P〈 0 .05） .For the comparison of Tmax and T1/2 ,there were no difference among the allele AA/ins ,AG/ins-del and GG/del（P〉0 .05） .Conclusion There was no effect of the polymorphism rs2282143 on metformin pharmacokinetics .The polymorphisms rs628031 and rs36056065 that were in completely linkage disequilibrium significantly associated with metformin pharmacokinetics .