Metformin is a widely used oral anti-diabetic, but the molecular mechanism(s) of its gastrointestinal membrane permeation remains unclear. Here, we examined the role of carnitine/organic cation transporter OCTN1/SLC22A4, which is localized on apical membranes of small intestine in mice and humans, in metformin absorption. The maximum plasma concentration (Cmax ) after oral administration of metformin (50 mg/kg) in octn1 gene knockout mice (octn1 (-/-) ) was higher than that in wild-type mice, with only a minimal difference in terminal half-life, but Cmax in octn1(-/-) mice given a higher dose (175 mg/kg) was lower than that in wild-type mice. Systemic elimination of metformin after intravenous administration was similar in the two strains, suggesting the possible involvement of OCTN1 in the gastrointestinal absorption. OCTN1-mediated uptake of metformin was observed in human embryonic kidney 293 cells transfected with mouse OCTN1 gene, but much lower than the uptake of the typical substrate [(3) H]ergothioneine (ERGO). In particular, the distribution volume for OCTN1-mediated uptake increased markedly and then tended to decrease as the metformin concentration was increased. Efflux of metformin preloaded in intestinal epithelial cell line Caco-2 was inhibited by ERGO. Overall, the present findings suggest that OCTN1 transports metformin and may be involved in its oral absorption in small intestine.
Keywords: ADME; drug transport; oral absorption; organic cation transporter; pharmacokinetics; renal excretion.
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