aInstitute of Public Health, Clinical Pharmacology, University of Southern Denmark bDepartment of Clinical Genetics cDepartment of Clinical Chemistry and Pharmacology dDepartment of Endocrinology, Odense University Hospital, Odense, Denmark.
Pharmacogenet Genomics. 2013 Oct;23(10):526-34. doi: 10.1097/FPC.0b013e328364a57d.
The aim of this study was to determine the association between the renal clearance (CL(renal)) of metformin in healthy Caucasian volunteers and the single-nucleotide polymorphism (SNP) c.808G>T (rs316019) in OCT2 as well as the relevance of the gene-gene interactions between this SNP and (a) the promoter SNP g.-66T>C (rs2252281) in MATE1 and (b) the OCT1 reduced-function diplotypes.
Fifty healthy volunteers genotyped for the c.808G>T were enrolled in the study. The distribution was 25 GG, 20 GT, and 5 TT volunteers. The pharmacokinetics of a 500 mg single oral dose of metformin was studied.
When analyzed alone, the c.808 (G>T) affected neither the CL(renal) nor the secretory clearance (CL(sec)) of metformin. However, both CL(renal) and CL(sec) were increased for the volunteers with minor alleles in c.808 (G>T) who were also homozygous for the reference variant g.-66T>C: CL(renal): GG, GT, and TT: 28.1, 34.5, and 44.8 l/h (P = 0.004), respectively and CL(sec): GG, GT, and TT: 21.4, 27.8, and 37.6 l/h (P = 0.005), respectively. In the volunteers with minor alleles in c.808 (G>T) who were also heterozygous for g.-66T>C, both CL(renal) and CL(sec) were found to be reduced (P < 0.028) when compared with volunteers with minor alleles in c.808 (G>T) carrying the g.-66T>C reference genotype.
We report counteracting effects of the c.808 (G>T) and g.-66T>C on the renal elimination of metformin. When adjusted for the genetic variation g.-66T>C, our results suggest that c.808 (G>T) could have a dominant genotype to phenotype correlation.
本研究旨在确定健康白种人志愿者中二甲双胍的肾清除率（CL（renal））与单核苷酸多态性（SNP）c.808G>T（rs316019）之间的关系，以及该 SNP 与（a）MATE1 启动子 SNP g.-66T>C（rs2252281）和（b）OCT1 功能降低二倍型之间的基因-基因相互作用的相关性。
本研究纳入了 50 名接受 c.808G>T 基因分型的健康志愿者。分布情况为 25 名 GG、20 名 GT 和 5 名 TT 志愿者。研究了志愿者单次口服 500mg 二甲双胍的药代动力学。
当单独分析时，c.808（G>T）既不影响二甲双胍的 CL（renal），也不影响其分泌清除率（CL（sec））。然而，c.808（G>T）中的次要等位基因且同时为 g.-66T>C 参考变体纯合的志愿者的 CL（renal）和 CL（sec）均增加：CL（renal）：GG、GT 和 TT 分别为 28.1、34.5 和 44.8 l/h（P = 0.004），CL（sec）：GG、GT 和 TT 分别为 21.4、27.8 和 37.6 l/h（P = 0.005）。在 c.808（G>T）中的次要等位基因且同时为 g.-66T>C 杂合的志愿者中，与携带 g.-66T>C 参考基因型的 c.808（G>T）中的次要等位基因的志愿者相比，CL（renal）和 CL（sec）均降低（P < 0.028）。
我们报告了 c.808（G>T）和 g.-66T>C 对二甲双胍肾清除率的拮抗作用。当调整遗传变异 g.-66T>C 时，我们的结果表明 c.808（G>T）可能具有显性基因型与表型相关性。
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