title: A comprehensive study demonstrating that p-glycoprotein function is directly affected by changes in pH: implications for intestinal pH and effects on drug absorption.
abstract: The purpose of this study was to investigate whether changes in the pH of the gastrointestinal tract can directly affect P-glycoprotein (P-gp) function. The effect of changes in extracellular pH on P-gp functionality was examined by testing colchicine (a nonionizable P-gp substrate) in bidirectional Caco-2 and MDR1-Madine Darby canine kidney (MDCK) cell permeability assays, in which the pH of the apical and basolateral chambers was varied. Reduction of the pH from 7.4 to 5.0 and 4.5 markedly increased the apical-to-basolateral flux of colchicine and reduced the basolateral-to-apical flux. The efflux ratio for colchicine was reduced to 1.2 at pH 4.5, compared with values greater than 20 that were measured in the pH range of 5.5-7.4. A similar result was obtained when MDR1-MDCK cells were used in the bidirectional permeability studies. Other nonionizable P-gp substrates (digoxin, dexamethasone, paclitaxel, and etoposide) responded to acidic pH (4.5) in a manner similar to colchicine. Reduced P-gp ATPase activity is a reason for the diminished P-gp function observed at pH 4.5.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas.
authors.forename: Pallabi
authors.initials: P
authors.lastname: Mitra
authors.forename: Kenneth
authors.initials: K
authors.lastname: Audus
authors.forename: Gervan
authors.initials: G
authors.lastname: Williams
authors.forename: Mehran
authors.initials: M
authors.lastname: Yazdanian
authors.forename: Deborah
authors.initials: D
authors.lastname: Galinis
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D018938:Caco-2 Cells; D003078:Colchicine / Q000378:metabolism; D004077:Digoxin / Q000378:metabolism; D004285:Dogs; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D010539:Permeability; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D004077:Digoxin; D000255:Adenosine Triphosphate; D003078:Colchicine