Mechanisms of transport of quinapril in Caco-2 cell monolayers: comparison with cephalexin

Purpose: To determine the transport mechanisms of quinapril and cephalexin in Caco-2 cell monolayers, a Cell Culture model of the human small intestinal epithelium.

Methods: Uptake, transepithelial transport and intracellular accumulations of these two drugs were measured using Caco-2 cell monolayers grown onto Millicells and magnetically stirred diffusion chambers.

Results: Transepithelial transport, apical (AP)4 uptake and intracellular accumulation of both drugs depended on the maintenance of a transepithelial proton gradient and temperature of the medium. However, quinapril transport and accumulation, which did not display a maximum at approximately pH 6, was more sensitive to proton gradient change, whereas cephalexin transport was more sensitive to concentration change (range 0.5-5 mM). In addition, quinapril (1 mM) transport was decreased significantly (p < 0.05) by 10 mM cephalexin, loracarbef, Gly-Pro and Phe-Pro, but not by enalapril; whereas cephalexin (0.1 mM) transport was decreased significantly (p < 0.05) by all four compounds. Similarly, AP quinapril (1 mM) uptake was also decreased by 10 mM loracarbef, Gly-Pro, cephalexin, and enalapril, but these inhibitory effects (20-50%) were quantitatively less than their inhibitory effects on cephalexin uptake (50-90%). Finally, the AP uptake of quinapril was also significantly (p < 0.05) inhibited by FCCP (10 micrograms/ml), amiloride (0.5 mM), DEP (0.5 mM), and staurosporine (5 nM).

Conclusions: The transport of quinapril in the Caco-2 cells is via a combination of the carrier-mediated proton gradient-dependent peptide transporter and passive diffusion.