Abstract
Metformin is a widely used oral antihyperglycemic drug for the treatment of type II diabetes mellitus. The intestinal absorption of metformin is dose-dependent and involves an active, saturable uptake process. Metformin has been shown to be transported by the human organic cation transporters 1 and 2 (hOCT1-2). We recently cloned and characterized a novel proton-activated organic cation transporter, plasma membrane monoamine transporter (PMAT). We previously showed that PMAT transports many classic organic cations (e.g., monoamine neurotransmitters, 1-methyl-4-phenylpyridinium) in a pH-dependent manner and its mRNA is expressed in multiple human tissues. The goal of this study is to investigate whether metformin is a substrate of PMAT and whether PMAT plays a role in the intestinal uptake of metformin. Using Madin-Darby canine kidney cells stably expressing human PMAT, we showed that metformin is avidly transported by PMAT, with an apparent affinity (Km = 1.32 mM) comparable to those reported for hOCT1-2. Interestingly, the concentration-velocity profile of PMAT-mediated metformin uptake is sigmoidal, with a Hill coefficient of 2.64. PMAT-mediated metformin transport is greatly stimulated by acidic pH, with the uptake rate being ∼4-fold higher at pH 6.6 than at pH 7.4. Using a polyclonal antibody against PMAT, we showed that the PMAT protein (58 kDa) was expressed in human small intestine and concentrated on the tips of the mucosal epithelial layer. Taken together, our results suggest that PMAT transports metformin, is expressed in human intestine, and may play a role in the intestinal absorption of metformin and possibly other cationic drugs.
Footnotes
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This work was supported by a grant (GM66233) from the National Institutes of Health. M.Z. is partially supported by a predoctoral fellowship from Eli Lilly Foundation.
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doi:10.1124/dmd.107.015495.
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ABBREVIATIONS: OCT, organic cation transporter; MPP+, 1-methyl-4-phenylpyridinium; MDCK, Madin-Darby canine kidney; PMAT, plasma membrane monoamine transporter; KRH, Krebs-Ringer-Henseleit; RT-PCR, reverse-transcription polymerase chain reaction; PBS, phosphate-buffered saline.
- Received February 28, 2007.
- Accepted June 25, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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