Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 102, Issue 9, Pages 3407-3417Publisher
WILEY-BLACKWELL
DOI: 10.1002/jps.23595
Keywords
oral absorption; organic cation transporter; pharmacokinetics; ADME; drug transport; renal excretion
Funding
- Ministry of Education, Science and Culture of Japan
- Advanced research for medical products Mining Programme of the National Institute of Biomedical Innovation
- Grants-in-Aid for Scientific Research [24390040, 25460092] Funding Source: KAKEN
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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 (C-max) 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 C-max in octn1(-/-) mice given a higher dose (175 mg/kg) was lower than that in wildtype 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 [H-3] 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. (C) 2013 Wiley Periodicals, Inc.
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