Mechanisms of transport of quinapril in Caco-2 cell monolayers: comparison with cephalexin.
OBJECTIVE
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.
D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism*; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000378:metabolism; D002506:Cephalexin / Q000378:metabolism*; D002511:Cephalosporins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004058:Diffusion; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007546:Isoquinolines / Q000378:metabolism*; D007700:Kinetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D000077583:Quinapril; D013696:Temperature; D044005:Tetrahydroisoquinolines; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D002352:Carrier Proteins; D002511:Cephalosporins; D007546:Isoquinolines; D010455:Peptides; D044005:Tetrahydroisoquinolines; D002506:Cephalexin; D000077583:Quinapril