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Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin.
J Pharm Sci. 2013 Sep; 102(9):3407-17.JP

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+Show Affiliations

Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23666872

Citation

Nakamichi, Noritaka, et al. "Involvement of Carnitine/organic Cation Transporter OCTN1/SLC22A4 in Gastrointestinal Absorption of Metformin." Journal of Pharmaceutical Sciences, vol. 102, no. 9, 2013, pp. 3407-17.
Nakamichi N, Shima H, Asano S, et al. Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin. J Pharm Sci. 2013;102(9):3407-17.
Nakamichi, N., Shima, H., Asano, S., Ishimoto, T., Sugiura, T., Matsubara, K., Kusuhara, H., Sugiyama, Y., Sai, Y., Miyamoto, K., Tsuji, A., & Kato, Y. (2013). Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin. Journal of Pharmaceutical Sciences, 102(9), 3407-17. https://doi.org/10.1002/jps.23595
Nakamichi N, et al. Involvement of Carnitine/organic Cation Transporter OCTN1/SLC22A4 in Gastrointestinal Absorption of Metformin. J Pharm Sci. 2013;102(9):3407-17. PubMed PMID: 23666872.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin. AU - Nakamichi,Noritaka, AU - Shima,Hiroyo, AU - Asano,Satoshi, AU - Ishimoto,Takahiro, AU - Sugiura,Tomoko, AU - Matsubara,Kazuki, AU - Kusuhara,Hiroyuki, AU - Sugiyama,Yuichi, AU - Sai,Yoshimichi, AU - Miyamoto,Ken-Ichi, AU - Tsuji,Akira, AU - Kato,Yukio, Y1 - 2013/05/10/ PY - 2012/12/23/received PY - 2013/04/16/revised PY - 2013/04/18/accepted PY - 2013/5/14/entrez PY - 2013/5/15/pubmed PY - 2014/3/7/medline KW - ADME KW - drug transport KW - oral absorption KW - organic cation transporter KW - pharmacokinetics KW - renal excretion SP - 3407 EP - 17 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 102 IS - 9 N2 - 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. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/23666872/Involvement_of_carnitine/organic_cation_transporter_OCTN1/SLC22A4_in_gastrointestinal_absorption_of_metformin_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(15)30945-X DB - PRIME DP - Unbound Medicine ER -