title: Four cation-selective transporters contribute to apical uptake and accumulation of metformin in Caco-2 cell monolayers.
abstract: Metformin is the frontline therapy for type II diabetes mellitus. The oral bioavailability of metformin is unexpectedly high, between 40 and 60%, given its hydrophilicity and positive charge at all physiologic pH values. Previous studies in Caco-2 cell monolayers, a cellular model of the human intestinal epithelium, showed that during absorptive transport metformin is taken up into the cells via transporters in the apical (AP) membrane; however, predominant transport to the basolateral (BL) side occurs via the paracellular route because intracellular metformin cannot egress across the BL membrane. Furthermore, these studies have suggested that the AP transporters can contribute to intestinal accumulation and absorption of metformin. Transporter-specific inhibitors as well as a novel approach involving a cocktail of transporter inhibitors with overlapping selectivity were used to identify the AP transporters that mediate metformin uptake in Caco-2 cell monolayers; furthermore, the relative contributions of these transporters in metformin AP uptake were also determined. The organic cation transporter 1, plasma membrane monoamine transporter (PMAT), serotonin reuptake transporter, and choline high-affinity transporter contributed to approximately 25%, 20%, 20%, and 15%, respectively, of the AP uptake of metformin. PMAT-knockdown Caco-2 cells were constructed to confirm the contribution of PMAT in metformin AP uptake because a PMAT-selective inhibitor is not available. The identification of four intestinal transporters that contribute to AP uptake and potentially intestinal absorption of metformin is a significant novel finding that can influence our understanding of metformin pharmacology and intestinal drug-drug interactions involving this highly prescribed drug.
authors.affiliation: Division of Molecular Pharmaceutics (T.H., W.R.P., C.L.C.) and Division of Pharmacotherapy and Experimental Therapeutics (H.C., R.S.E., D.R.T.), UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Tianxiang Kevin
authors.initials: TK
authors.lastname: Han
authors.affiliation: Division of Molecular Pharmaceutics (T.H., W.R.P., C.L.C.) and Division of Pharmacotherapy and Experimental Therapeutics (H.C., R.S.E., D.R.T.), UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: William R
authors.initials: WR
authors.lastname: Proctor
authors.affiliation: Division of Molecular Pharmaceutics (T.H., W.R.P., C.L.C.) and Division of Pharmacotherapy and Experimental Therapeutics (H.C., R.S.E., D.R.T.), UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Chester L
authors.initials: CL
authors.lastname: Costales
authors.affiliation: Division of Molecular Pharmaceutics (T.H., W.R.P., C.L.C.) and Division of Pharmacotherapy and Experimental Therapeutics (H.C., R.S.E., D.R.T.), UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Hao
authors.initials: H
authors.lastname: Cai
authors.affiliation: Division of Molecular Pharmaceutics (T.H., W.R.P., C.L.C.) and Division of Pharmacotherapy and Experimental Therapeutics (H.C., R.S.E., D.R.T.), UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Everett
authors.affiliation: Division of Molecular Pharmaceutics (T.H., W.R.P., C.L.C.) and Division of Pharmacotherapy and Experimental Therapeutics (H.C., R.S.E., D.R.T.), UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina dhiren_thakker@unc.edu.
authors.forename: Dhiren R
authors.initials: DR
authors.lastname: Thakker
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D018938:Caco-2 Cells; D033705:Equilibrative Nucleoside Transport Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism; D008687:Metformin / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
chemical_list: D026923:Amino Acid Transport Systems, Basic; D033705:Equilibrative Nucleoside Transport Proteins; D007004:Hypoglycemic Agents; D026901:Membrane Transport Proteins; D027702:Organic Cation Transporter 1; C495988:SLC29A4 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C065637:choline transporter; D008687:Metformin