PURPOSE: The purpose of this study was to investigate the pH-dependent passive and active transport of weakly basic drugs across the human intestinal epithelium. METHODS: The bidirectional pH-dependent transport of weak bases was studied in Caco-2 cell monolayers in the physiologic pH range of the gastrointestinal tract. RESULTS: A net secretion of atenolol and metoprolol was observed when a pH gradient was applied. However, the bidirectional transport of both compounds was equal in the nongradient system. Hence, at lower apical than basolateral pH a change in passive transport caused by an imbalance in the concentration of the uncharged drug species resulted in a "false" asymmetry (efflux ratio). Furthermore, a mixture of pH-dependent passive and active efflux was found for the P-glycoprotein (P-gp, MDR1, ABCB1) substrates, talinolol and quinidine, but not for the neutral drug, digoxin. However, the clinically important digoxin-quinidine interaction depended on the presence of a pH gradient. Hence, the degree of interaction depends on the amount of quinidine available at the binding site of the P-gp. CONCLUSIONS: Active efflux of weak bases can only be accounted for when the fraction of unionized drug species is equal in all compartments because the transport is biased by a pH-dependent passive component. However, this component may take part in vivo and contribute to drug-drug interactions involving P-gp.
PURPOSE: The purpose of this study was to investigate the pH-dependent passive and active transport of weakly basic drugs across the human intestinal epithelium. METHODS: The bidirectional pH-dependent transport of weak bases was studied in Caco-2 cell monolayers in the physiologic pH range of the gastrointestinal tract. RESULTS: A net secretion of atenolol and metoprolol was observed when a pH gradient was applied. However, the bidirectional transport of both compounds was equal in the nongradient system. Hence, at lower apical than basolateral pH a change in passive transport caused by an imbalance in the concentration of the uncharged drug species resulted in a "false" asymmetry (efflux ratio). Furthermore, a mixture of pH-dependent passive and active efflux was found for the P-glycoprotein (P-gp, MDR1, ABCB1) substrates, talinolol and quinidine, but not for the neutral drug, digoxin. However, the clinically important digoxin-quinidine interaction depended on the presence of a pH gradient. Hence, the degree of interaction depends on the amount of quinidine available at the binding site of the P-gp. CONCLUSIONS: Active efflux of weak bases can only be accounted for when the fraction of unionized drug species is equal in all compartments because the transport is biased by a pH-dependent passive component. However, this component may take part in vivo and contribute to drug-drug interactions involving P-gp.
Authors: Duxin Sun; Hans Lennernas; Lynda S Welage; Jeffery L Barnett; Christopher P Landowski; David Foster; David Fleisher; Kyung-Dall Lee; Gordon L Amidon Journal: Pharm Res Date: 2002-10 Impact factor: 4.200
Authors: J Fallingborg; L A Christensen; M Ingeman-Nielsen; B A Jacobsen; K Abildgaard; H H Rasmussen Journal: Aliment Pharmacol Ther Date: 1989-12 Impact factor: 8.171
Authors: Kiyohiko Sugano; Manfred Kansy; Per Artursson; Alex Avdeef; Stefanie Bendels; Li Di; Gerhard F Ecker; Bernard Faller; Holger Fischer; Grégori Gerebtzoff; Hans Lennernaes; Frank Senner Journal: Nat Rev Drug Discov Date: 2010-08 Impact factor: 84.694