Functional characterization of the human organic cation transporter 2 variant p.270Ala>Ser. Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] Journal article

The organic cation transporter 2 (OCT2, SLC22A2) plays an important role for renal drug elimination. Recent clinical studies indicate an impact of the frequent non-synonymous c.808G>T (p.270Ala>Ser) polymorphism on renal clearance of metformin and the extent of the metformin-cimetidine interaction. The role of this polymorphism for renal disposition of endogenous compounds and drugs other than metformin has not been investigated. In addition, it is unclear whether the observed genotype-dependence of an OCT2-mediated drug-drug interaction might occur also with other OCT inhibitors. To address these issues we generated HEK cells stably expressing wildtype OCT2 or the p.270Ala>Ser variant. No differences in protein expression levels and membrane incorporation pattern were observed between the two cell lines. The p.270Ala>Ser variant significantly impaired uptake kinetics of MPP(+), dopamine, norepinephrine, and propranolol. Vmax values were significantly reduced for all four compounds mediated by the p.270Ala>Ser variant compared to wildtype OCT2. In addition, a significant difference in the affinity to wildtype and mutant OCT2 was observed for dopamine (Km dopamine: 932+/-77 vs 1285+/-132 microM). Moreover, out of a set of 27 compounds p.270Ala>Ser OCT2 was significantly less sensitive to inhibition by cimetidine, flurazepam, metformin, mexiletine, propranolol, and verapamil than wildtype OCT2 (e.g. for propranolol: IC50 wildtype vs p.270Ala>Ser 189 vs 895 microM, P<0.001). Our results indicate that the common OCT2 c.808G>T SNP significantly alters uptake of endogenous compounds and drugs. Moreover, for selected compounds the extent of OCT2-mediated drug interactions could depend on OCT2 c.808G>T genotype.

Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos]