![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication March 6, 2007.
Revised June 22, 2007.
Accepted for publication June 25, 2007.
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, MPP+) 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 MDCK 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.
Key words:
absorption, drug transport, intestinal transport, membrane barriers, oral absorption, organic cation transport, transporters
This article has been cited by other articles:
|
|
 |
|
  K. Zhou, L. A. Donnelly, C. H. Kimber, P. T. Donnan, A. S.F. Doney, G. Leese, A. T. Hattersley, M. I. McCarthy, A. D. Morris, C. N.A. Palmer, et al. Reduced-Function SLC22A1 Polymorphisms Encoding Organic Cation Transporter 1 and Glycemic Response to Metformin: A GoDARTS Study Diabetes, June 1, 2009; 58(6): 1434 - 1439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Xia, M. Zhou, T. F. Kalhorn, H. T. B. Ho, and J. Wang Podocyte-specific expression of organic cation transporter PMAT: implication in puromycin aminonucleoside nephrotoxicity Am J Physiol Renal Physiol, June 1, 2009; 296(6): F1307 - F1313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. R. Proctor, D. L. Bourdet, and D. R. Thakker Mechanisms Underlying Saturable Intestinal Absorption of Metformin Drug Metab. Dispos., August 1, 2008; 36(8): 1650 - 1658. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
