Cation-selective Apical Transporters Mediate an Intestinal Cycling Mechanism of Metformin that Enhances its Paracellular Oral Absorption in Mice Public Deposited

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  • March 22, 2019
  • Costales, Chester Lee
    • Affiliation: Eshelman School of Pharmacy
  • Metformin is the most widely prescribed drug for type 2 diabetes mellitus; yet its in vivo mechanism of oral absorption has not been elucidated. A pKa of 12.4 and logDpH6.0 of -6.13 suggest metformin is a hydrophilic cation at all physiologic pHs, limiting its ability to cross biological membranes. However, metformin is well-absorbed with an oral bioavailability ranging from ~40-60% in man. Previous in vitro studies conducted using the Caco-2 Transwell® model of intestinal absorption demonstrated efficient transporter-mediated metformin apical uptake and efflux and poor basolateral egress. Kinetic modeling of these results suggested absorptive transport is predominantly paracellular, and led to the development of a novel mechanism of absorption stating that during oral absorption of metformin, transporter-mediated apical uptake and a lack of basolateral efflux leads to intestinal drug accumulation. Changes in luminal drug concentration as a result of gastrointestinal transit leads to apical efflux of metformin and its enhanced paracellular absorption. Studies presented in this dissertation evaluate this novel metformin absorption mechanism in a mouse model. Gene expression of the mouse orthologs of putative human metformin transporters, namely organic cation transporter 1-3 (mOct1-3), multidrug and toxin extrusion 1 (mMate1), and plasma membrane monoamine transporter (mPmat), was characterized in mouse small intestine. Stable cell lines singly-expressing these transporters were generated, and metformin uptake kinetics for each transporter was determined. Pentamidine, quinidine, and desipramine, were identified as pan transporter inhibitors and were used in subsequent mouse studies. Absorptive transport of metformin in ex vivo experiments using mouse intestinal tissue was similar to results previously reported for Caco-2 cell monolayers, showing high transporter-mediated apical uptake compared to apical-to-basolateral transport. Metformin orally co-administered with pentamidine demonstrated that the intestinal accumulation and absorption of metformin is transporter-mediated. Attenuation of metformin apical efflux in the intestine after oral dosing showed a decreased metformin absorption rate, suggesting an important role for apical efflux of metformin during its oral absorption. Collectively, these studies provide strong circumstantial evidence that metformin is absorbed through the hypothesized mechanism, which can account for the intestinal accumulation and oral pharmacokinetics of metformin observed in human and animal studies.
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  • In Copyright
  • Thakker, Dhiren
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2013

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