Genetic variants of organic cation transporter 2 (OCT2) significantly reduce metformin uptake in oocytes

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
I S SongJ G Shin

Abstract

1. The authors sought to evaluate the contribution of organic cation transporters (OCTs) to the renal tubular transport of metformin using LLC-PK1 cells as an in vitro model for the renal proximal tubule, and to investigate the effects of three non-synonymous genetic variants of OCT2 on the transport activity of metformin in vitro using an oocyte over-expression system. 2. The basolateral-to-apical transport of metformin was significantly greater than the apical-to-basolateral transport and showed concentration dependency with the kinetic parameters: maximum transport rate (V(max)), 922 pmol min(-1) per 5 x 10(5) cells; Michaelis-Menten constant (K(m)), 393 microM; intrinsic clearance (CL(int)), 2.35 microl min(-1) per 5 x 10(5) cells; and diffusion constant (K(d)), 0.33 microl min(-1) per 5 x 10(5) cells. The basolateral-to-apical transport of metformin was inhibited by phenoxybenzamine, an inhibitor of OCTs, but not by cyclosporine A, MK571, or fumitremorgin C, which are inhibitors of P-glycoprotein, multidrug resistance proteins (MRPs), and breast cancer resistance protein (BCRP), respectively, suggesting that OCTs play a role in renal tubular secretion of metformin. 3. Metformin uptake was much greater in oocytes expressing...Continue Reading

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