High Permeability of the Anionic Form Restricts Accumulation of Indomethacin by Cultured Gastric Surface Epithelial Cells Exposed to Low Apical Ph.
From: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
European journal of pharmacology
- Publish Date: Nov 2006
- ISSN: 0014-2999
- Volume: 549
- Issue: 1-3
- Pages: 41-9
- Medium: Print
- Language: English
- Citation (JAMA): Kavvada Klairi M, Murray James G, Moore Vanessa A, et al. High Permeability of the Anionic Form Restricts Accumulation of Indomethacin by Cultured Gastric Surface Epithelial Cells Exposed to Low Apical Ph.. Eur. J. Pharmacol. Nov 2006;549:41-9
Abstract
The ‘ion-trapping’ hypothesis suggests that the intracellular concentration of acidic non-steroidal anti-inflammatory drugs in gastric epithelial cells could be much higher than in the gastric lumen, and that such accumulation could contribute to their gastrotoxicity. Our aim was to examine the effect of the pH of the apical medium on the apical to basal transfer of the acidic drug indomethacin (pKa 4.5) across a gastric mucous epithelial cell monolayer, and to determine whether indomethacin accumulated in cells exposed to a low apical pH. Guinea-pig gastric mucous epithelial cells were grown on porous membrane culture inserts (Transwells) for 72 h. Transfer and accumulation of [14C] indomethacin were assessed by scintillation counting. Transfer of [3H]mannitol and measurement of trans-epithelial electrical resistance were used to assess integrity of the monolayer. Distribution of [14C] urea was used to estimate the intracellular volume of the monolayer. The monolayer was not disrupted by exposure of the apical face to media of pH>or=3, or by indomethacin. Transfer of indomethacin (12 microM) to the basal medium increased with decreasing apical medium pH. The apparent permeability of the undissociated acid was estimated to be five times that of the anion. The intracellular concentration of indomethacin was respectively 5.3, 4.1 and 4.3 times that in the apical medium at pH 5.5, 4.5 and 3.0. In conclusion, this study represents the first direct demonstration that indomethacin accumulates in gastric epithelial cells exposed to low apical pH. However, accumulation of indomethacin was moderate and the predictions of the ion-trapping hypothesis were not met, probably due to the substantial permeability of anionic indomethacin across membranes.
Mesh Headings (Keywords): Animals, Anions, Anti-Inflammatory Agents, Non-Steroidal, Biological Transport, Cell Membrane Permeability, Cells, Cultured, Dose-Response Relationship, Drug, Epithelial Cells, Gastric Mucosa, Guinea Pigs, Hydrogen-Ion Concentration, Indomethacin, Intracellular Fluid, Mannitol
Check for Full Text / PubMed Unique Identifier (PMID): 16996496
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