Effects of Xhosa Specific Solute Carrier Family 22-member 2 Haplotypes on the Cellular Uptake of Metformin and Cimetidine

Abstract

Background Metformin remains the cornerstone for the treatment of type 2 diabetes mellitus. Although the mechanism in which this drug elicits its therapeutic effects is unknown, studies have shown that solute carrier transporters play an important role in the transport and distribution of metformin. Genetic variation(s) in solute carrier genes have been found to play an important role in the variation of metformin efficacy and disposition observed in populations. The aim of this study was to determine the cellular uptake efficiency of metformin in SLC22A2 coding haplotypes of an indigenous South African population. Methods and Results To determine metformin and cimetidine cellular uptake in transiently transfected HEK-293 cells, an ultra high-performance liquid chromatography method was developed and used to quantitate substrate concentration(s). Haplotypes 3 and 4 showed decreased metformin uptake, and haplotypes 2 and 5 displayed increased metformin uptake in comparison to haplotype 1 (i.e. wildtype haplotype). Haplotypes 2–5 showed decreased uptake of cimetidine in comparison to haplotype 1, implying a reduced sensitivity to the inhibition of cimetidine. In all haplotypes, no significant transport was observed for metformin and cimetidine. Spearman’s correlation analysis indicated a positive but non-significant correlation (r_s = 0.60; p = 0.28) across haplotypes for the active uptake of metformin and cimetidine. Passive permeability of metformin is favoured in haplotypes 3 and 5, whilst the remaining haplotypes demonstrate higher passive permeability ratios in favour of cimetidine. Conclusion Haplotype 4, which is characterised by the non-synonymous single nucleotide polymorphisms rs316019 and rs8177517, demonstrates potential impaired metformin transport.