Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin.
Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin.
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DOI：
10.1097/fpc.0b013e32832cc7e9
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发表时间：
2009-07
影响因子：
2.6
通讯作者：
Giacomini KM
中科院分区：
文献类型：
--
作者：
Chen Y;Li S;Brown C;Cheatham S;Castro RA;Leabman MK;Urban TJ;Chen L;Yee SW;Choi JH;Huang Y;Brett CM;Burchard EG;Giacomini KM
这项研究的目的是确定有机阳离子转运体(OCT2)的一个基因变异OCT2-808G/T，它导致氨基酸变化A270S对抗糖尿病药物二甲双胍的药代动力学的影响。在稳定表达空载体(Mock)、参考OCT2-808G和突变体OCT2-808T的HEK-293细胞中进行二甲双胍摄取。研究对象为已知OCT2基因[OCT2参考等位基因纯合子14例(808G/G)，变异等位基因杂合9例(808G/T，*3D)]的健康个体。采用高效液相色谱-串联质谱法测定血浆和尿液中二甲双胍浓度。同时还测定了血浆和尿液中的肌酐水平。对两组的药代动力学参数进行评估。我们观察到，在HEK-293稳定转染的细胞中，OCT2-808T比参考OCT2具有更大的转运二甲双胍的能力。研究了23名高加索和非裔美国人血统的健康志愿者的二甲双胍药代动力学特征。我们观察到变异等位基因杂合子(808G/T)和参考等位基因纯合子(808G/G)志愿者的肾清除量和净分泌量有显著差异(p<；0.005)。多因素分析显示，OCT2基因是二甲双胍CLR和SrCLR的显著预测因子(p<；0.01)。我们的结论是，OCT2基因变异在健康志愿者二甲双胍的CLR和SrCLR中起重要作用。
The goal of this study was to determine the effect of a genetic variant in the organic cation transporter (OCT2), OCT2-808G/T, which results in an amino acid change, A270S, on the pharmacokinetics of the anti-diabetic drug, metformin. The uptake of metformin was performed in stably transfected HEK-293 cells expressing the empty vector (MOCK), the reference OCT2-808G and the variant OCT2-808T. Healthy individuals with known OCT2 genotypes [fourteen homozygous for the OCT2 reference allele (808G/G) and nine heterozygous for the variant allele (808G/T, *3D)] were recruited into this study. Metformin concentrations in plasma and urine were measured by liquid chromatography-tandem mass spectrometry method. Creatinine levels were also measured in plasma and urine. Pharmacokinetic parameters were evaluated for both groups. We observed that in HEK-293 stably transfected cells, OCT2-808T had a greater capacity to transport metformin than did the reference OCT2. Metformin pharmacokinetics were characterized in twenty-three healthy volunteers of Caucasian and African American ancestries. We observed that the renal clearance (CLR) and the net secretion (SrCLR) of metformin were significantly different between the volunteers heterozygous for the variant allele (808G/T), and the volunteers homozygous for the reference allele (808G/G) (p<0.005). Multivariate analysis revealed that OCT2 genotype was a significant predictor of CLR and SrCLR of metformin (p<0.01). We conclude that genetic variation in OCT2 plays an important role in the CLR and SrCLR of metformin in healthy volunteers.