SUITABILITY OF ENALAPRIL AS A PROBE OF THE DIPEPTIDE TRANSPORTER SYSTEM - IN-VITRO AND IN-VIVO STUDIES

Purpose. Previous in situ and in vitro studies indicated that the inte stinal absorption of enalapril is a saturable carrier-mediated process via the dipeptide transporter system (DTS); however, the oral absorpt ion of enalapril has not been reported to be a saturable process in vi vo. Our objectives were to: 1) evaluate the suitability of enalapril a s a probe of the DTS, and 2) compare various experimental models as th ey pertain to studying the DTS. Methods. The in vitro uptake of enalap ril by rat intestinal rings and permeability across Caco-2 cells were studied as a function of concentration and in the presence of compound s that are known substrates of the DTS. The effect of enalapril on the uptake of [H-3]-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 ov er a wide dose range. Results. In vitro intestinal uptake/permeability of enalapril was not saturable nor inhibited by beta-lactam antibioti cs, gly-L-pro, or SQ-29852. Moreover, a 20,000-fold molar excess of en alapril did not inhibit the uptake of [H-3]-gly-L-pro by Caco-2 cells. The in vivo studies in rats and dogs did not demonstrate saturable ab sorption. Conclusions. The present in vitro and in vivo results indica ted that enalapril is primarily absorbed by a non-saturable, passive d iffusion process and it is not a suitable model compound for studying the DTS.