title: Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin.
abstract: 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.
authors.affiliation: Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Nakamichi
authors.forename: Hiroyo
authors.initials: H
authors.lastname: Shima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Asano
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sugiura
authors.forename: Kazuki
authors.initials: K
authors.lastname: Matsubara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuji
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008687:Metformin / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D051379:Mice; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins; D027981:Symporters
chemical_list: D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; C491659:Slc22a4 protein, mouse; D027981:Symporters; D008687:Metformin
keywords: ADME; drug transport; oral absorption; organic cation transporter; pharmacokinetics; renal excretion