title: Why Does the Intestine Lack Basolateral Efflux Transporters for Cationic Compounds? A Provocative Hypothesis.
abstract: Transport proteins in intestinal epithelial cells facilitate absorption of nutrients/compounds that are organic anions, cations, and zwitterions. For two decades, we have studied intestinal absorption and transport of hydrophilic ionic compounds, with specific focus on transport properties of organic cations and their interactions with intestinal transporters and tight junction proteins. Our data reveal how complex interactions between a compound and transporters in intestinal apical/basolateral (BL) membranes and tight junction proteins define oral absorption, and that the BL membrane lacks an efflux transporter that can transport positively charged compounds. Based on our investigations of transport mechanisms of zwitterionic, anionic, and cationic compounds, we postulate that physicochemical properties of these ionic species, in relation to the intestinal micro pH environment, have exerted evolutionary pressure for development of transporters that can handle apical uptake/efflux of all 3 ionic species and BL efflux of anions and zwitterions, but such evolutionary pressure is lacking for development of a BL efflux transporter for cationic compounds. This review provides an overview of intestinal uptake/efflux transporters and describes our studies on intestinal transport of cationic, anionic, and zwitterionic drugs that led to hypothesize that there are no cation-selective BL efflux transporters in the intestine.
authors: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors: William R
authors: WR
authors: Proctor
authors: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors: Xin
authors: X
authors: Ming
authors: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors: David
authors: D
authors: Bourdet
authors: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors: Tianxiang Kevin
authors: TK
authors: Han
authors: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors: Ruth S
authors: RS
authors: Everett
authors: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599. Electronic address: dhiren_thakker@unc.edu.
authors: Dhiren R
authors: DR
authors: Thakker
mesh_terms: D000818:Animals; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008687:Metformin / Q000008:administration & dosage / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*
chemical_list: D027701:Organic Cation Transport Proteins; D008687:Metformin
keywords: drug transport; intestinal absorption; intestinal epithelia; metformin; organic cation transporter; transporters