PURPOSE: Previous in situ and in vitro studies indicated that the intestinal absorption of enalapril is a saturable carrier-mediated process via the dipeptide transporter system (DTS); however, the oral absorption of enalapril has not been reported to be a saturable process in vivo. Our objectives were to: 1) evaluate the suitability of enalapril as a probe of the DTS, and 2) compare various experimental models as they pertain to studying the DTS. METHODS: The in vitro uptake of enalapril by rat intestinal rings and permeability across Caco-2 cells were studied as a function of concentration and in the presence of compounds that are known substrates of the DTS. The effect of enalapril on the uptake of [3H]-glycyl-L-proline (gly-L-pro) by Caco-2 cells was also examined. In vivo studies were conducted in rats (1 to 50 mg/kg) and dogs (0.06 to 6 mg/kg) to evaluate the oral absorption of enalapril over a wide dose range. RESULTS: In vitro intestinal uptake/permeability of enalapril was not saturable nor inhibited by beta-lactam antibiotics, gly-L-pro, or SQ-29852. Moreover, a 20,000-fold molar excess of enalapril did not inhibit the uptake of [3H]-gly-L-pro by Caco-2 cells. The in vivo studies in rats and dogs did not demonstrate saturable absorption. CONCLUSIONS: The present in vitro and in vivo results indicated that enalapril is primarily absorbed by a non-saturable, passive diffusion process and it is not a suitable model compound for studying the DTS.
PURPOSE: Previous in situ and in vitro studies indicated that the intestinal absorption of enalapril is a saturable carrier-mediated process via the dipeptide transporter system (DTS); however, the oral absorption of enalapril has not been reported to be a saturable process in vivo. Our objectives were to: 1) evaluate the suitability of enalapril as a probe of the DTS, and 2) compare various experimental models as they pertain to studying the DTS. METHODS: The in vitro uptake of enalapril by rat intestinal rings and permeability across Caco-2 cells were studied as a function of concentration and in the presence of compounds that are known substrates of the DTS. The effect of enalapril on the uptake of [3H]-glycyl-L-proline (gly-L-pro) by Caco-2 cells was also examined. In vivo studies were conducted in rats (1 to 50 mg/kg) and dogs (0.06 to 6 mg/kg) to evaluate the oral absorption of enalapril over a wide dose range. RESULTS: In vitro intestinal uptake/permeability of enalapril was not saturable nor inhibited by beta-lactam antibiotics, gly-L-pro, or SQ-29852. Moreover, a 20,000-fold molar excess of enalapril did not inhibit the uptake of [3H]-gly-L-pro by Caco-2 cells. The in vivo studies in rats and dogs did not demonstrate saturable absorption. CONCLUSIONS: The present in vitro and in vivo results indicated that enalapril is primarily absorbed by a non-saturable, passive diffusion process and it is not a suitable model compound for studying the DTS.
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: Eva J Streekstra; Márton Kiss; Jeroen van den Heuvel; Johan Nicolaï; Petra van den Broek; Sanne M B I Botden; Martijn W J Stommel; Lara van Rijssel; Anna-Lena Ungell; Evita van de Steeg; Frans G M Russel; Saskia N de Wildt Journal: Clin Transl Sci Date: 2022-08-12 Impact factor: 4.438