Clinical pharmacogenetics of metformin: Role of genetic variations of metformin transporters on the renal clearance of metformin

Abstract

Metformin is an anti-diabetic agent used as first line therapy for Type II Diabetes. The clearance of metformin decreases with decreasing clearance of creatinine, but there is still considerable variation in the clearance of metformin to the clearance of creatinine. Recently, research has focused on the role that metformin transporters play in the absorption, distribution and elimination (primarily renal) of metformin. Aim: The aim of the present study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of selected metformin transporters and the clearance of metformin Methods: The pharmacokinetics and pharmacogenetics of 104 Type II Diabetics was studied. We examined 62 SNPs of the Organic Cation Transporter 1 (OCT1), Organic Cation Transporter 2 (OCT2), Multi-drug and Toxin Extrusion Protein 1 (MATE1) and Plasma Membrane Monoamine Transporter (PMAT). DNA was extracted from all patients using phenol-chloroform method, amplified by polymerase chain reaction, and analysed using SEQUENOM system. Plasma concentrations of metformin were assayed and metformin clearance calculated using Kinetica population pharmacokinetic analysis software. Statistical analysis was carried out on results using SPSS software. Results and Discussion: Creatinine clearance and age account for 40{%} of inter-individual variation in metformin clearance. The rs644992 and rs9457843 (OCT1 introns) SNP variants were associated with an increased ratio of metformin clearance: creatinine clearance compared to the reference genotype, however there was no significant increase in metformin clearance between the two genotype groups. The rs3822841 (OCT1 intron) and rs2289669 (MATE1 intron) SNP variants were associated with a significant increase in metformin clearance and the ratio of metformin clearance: creatinine clearance. The rs2289669 SNP variant results are in contrast with previous literature on healthy subjects which showed that the variant reduces metformin clearance or has no effect on metformin clearance. Conclusion: The rs3822841 (OCT intron) and rs2289669 (MATE 1 intron) SNP variants are strongly assosciated with an increase in metformin clearance and the ratio of metformin clearance: creatinine clearance and may explain inter-individual variation in metformin clearance. Additionally, we hypothesize that the diabetic state induces a change in metformin transport kinetics of the rs2289669 variant.