Genetic Basis for Variation in the Renal Elimination of Metformin

The drug, which is used in the treatment of Type II diabetes, has a narrow therapeutic range. Its net renal clearance by secretion (i.e., renal clearance minus filtration clearance) ranges from approximately 100 ml/min to 800ml/min in normal, healthy subjects. Although many factors may contribute to inter-individual variation in renal secretory clearance, initial estimates of heritability (greater than 0.6) suggest that genetic factors play an important role in the renal secretion of metformin. Available evidence supports the idea that hOCT2 is the primary transporter involved in the first-step of renal secretion of metformin, i.e., uptake from the blood to the tubule cell across the basolateral membrane. In particular, (a) hOCT2 is the primary organic cation transporter on the basolateral membrane of the human kidney; and (b) metformin interacts with and is translocated by hOCT2 in heterologous expression systems.

In recent studies, we identified four variants (M165I, A270S, R400C, and K432Q) with ethnic-specific allele frequencies ≥1% [6] that have altered function in studies in heterologous expression systems. In addition, we identified a common haplotype of hOCT2 and one haplotype that contain the non-synonymous cSNP, A270S. We will determine whether variability in the renal secretory clearance of the model organic cation, metformin, in healthy individuals is associated with genetic variation in hOCT2. In particular, we will determine whether the renal clearance of metformin differs in individuals who are homozygous for the common haplotype of OCT2 (OCT2*1) and those who are heterozygous for the less common haplotype OCT2*3D, which we have identified in a comprehensive screen of ethnically identified DNA samples. We will also determine whether individuals who are heterozygous for the less common OCT2 variants, M165I, R400C and K432Q, have reduced renal clearances of metformin.