QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.147918v1 329/1/185    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tsuda, M. Articles by Inui, K.-i. Search for Related Content PubMed PubMed Citation Articles by Tsuda, M. Articles by Inui, K.-i.

METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Involvement of Human Multidrug and Toxin Extrusion 1 in the Drug Interaction between Cimetidine and Metformin in Renal Epithelial Cells

Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan

In human proximal tubules, organic cations are taken up from blood into cells by human organic cation transporter 2 [hOCT2/solute carrier (SLC) 22A2] and then eliminated into the lumen by apical H⁺/organic cation antiporters, human multidrug and toxin extrusion 1 (hMATE1/SLC47A1) and hMATE2-K (SLC47A2). To evaluate drug interactions of cationic drugs in the secretion process, epithelial cells engineered to express both hOCT2 and hMATE transporters are required to simultaneously evaluate drug interactions with renal basolateral and apical organic cation transporters. In the present study, therefore, we assessed the drug interaction between cimetidine and metformin with double-transfected Madin-Darby canine kidney cells stably expressing both hOCT2 and hMATE1 as an in vitro model of the proximal tubular epithelial cells. The basolateral-to-apical transport and intracellular accumulation of [¹⁴C]metformin by a double transfectant were markedly inhibited by 1 mM cimetidine at the basolateral side. On the other hand, 1 µM cimetidine at the basolateral side moderately decreased the basolateral-to-apical transport of [¹⁴C]metformin and significantly increased the intracellular accumulation of [¹⁴C]metformin from the basolateral side, suggesting that cimetidine at a low concentration inhibits apical hMATE1, rather than basolateral hOCT2. Actually, in concentration-dependent inhibition studies by a single transporter expression system, such as human embryonic kidney 293 stably expressing hMATE1, hMATE2-K, or hOCT2, cimetidine showed higher affinity for hMATEs than for hOCT2. These results suggest that apical hMATE1 is involved in drug interactions between cimetidine and cationic compounds in the proximal tubular epithelial cells.

Address correspondence to: Dr. Ken-ichi Inui, Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: inui{at}kuhp.kyoto-u.ac.jp

This article has been cited by other articles:

				M. Tsuda, T. Terada, T. Mizuno, T. Katsura, J. Shimakura, and K.-i. Inui Targeted Disruption of the Multidrug and Toxin Extrusion 1 (Mate1) Gene in Mice Reduces Renal Secretion of Metformin Mol. Pharmacol., June 1, 2009; 75(6): 1280 - 1286. [Abstract] [Full Text] [PDF]