S D Flanagan1, L Z Benet. 1. Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco 94143-0446, USA.
Abstract
PURPOSE: To determine if intestinal secretion occurs for the poorly bioavailable diuretic, furosemide. METHODS: Jejunal segments of male Sprague-Dawley rats were mounted on diffusion chambers, and the permeation of furosemide was measured across the excised tissue in both directions. Studies were repeated using cultured epithelia from adenocarcinoma cells (Caco-2) grown on filter inserts mounted in 6-well plates. Temperature-dependence and chemical inhibition by indomethacin was also tested using the cell culture model. RESULTS: Net secretion from rat intestine of over 3-fold was observed for 20 microM furosemide. Net secretion of furosemide by Caco-2 cells was over 300% greater than for intestinal segments (10-fold vs. 3-fold). For both models, a decrease in furosemide transport in the direction of secretion was observed in the presence of indomethacin (100 microM), although only results using the Caco-2 cells showed in increase in the absorptive transport. Furosemide secretion from Caco-2 cells decreased with decrease in temperature from 37 degrees C to 4 degrees C, suggesting a carrier-mediated process. CONCLUSIONS: Furosemide appears to be secreted in the small intestine. These preliminary results indicate that furosemide bioavailability may be limited by an intestinal transporter.
PURPOSE: To determine if intestinal secretion occurs for the poorly bioavailable diuretic, furosemide. METHODS: Jejunal segments of male Sprague-Dawley rats were mounted on diffusion chambers, and the permeation of furosemide was measured across the excised tissue in both directions. Studies were repeated using cultured epithelia from adenocarcinoma cells (Caco-2) grown on filter inserts mounted in 6-well plates. Temperature-dependence and chemical inhibition by indomethacin was also tested using the cell culture model. RESULTS:Net secretion from rat intestine of over 3-fold was observed for 20 microM furosemide. Net secretion of furosemide by Caco-2 cells was over 300% greater than for intestinal segments (10-fold vs. 3-fold). For both models, a decrease in furosemide transport in the direction of secretion was observed in the presence of indomethacin (100 microM), although only results using the Caco-2 cells showed in increase in the absorptive transport. Furosemide secretion from Caco-2 cells decreased with decrease in temperature from 37 degrees C to 4 degrees C, suggesting a carrier-mediated process. CONCLUSIONS:Furosemide appears to be secreted in the small intestine. These preliminary results indicate that furosemide bioavailability may be limited by an intestinal transporter.
Authors: R Evers; G J Zaman; L van Deemter; H Jansen; J Calafat; L C Oomen; R P Oude Elferink; P Borst; A H Schinkel Journal: J Clin Invest Date: 1996-03-01 Impact factor: 14.808