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

• Published in: Pharmaceutical research 1995-08, Vol.12 (8), p.1120-1125
• Main Authors: MING HU, LIXING ZHENG, JIYUE CHEN, LIJUAN LIU, YANPING ZHU, DANTZIG, A. H, STRATFORD, R. E
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Angiotensin-Converting Enzyme Inhibitors - metabolism; Biological and medical sciences; Biological Transport, Active; Caco-2 Cells; Carrier Proteins - metabolism; Cephalexin - metabolism; Cephalosporins - metabolism; Chromatography, High Pressure Liquid; Diffusion; General pharmacology; Humans; Hydrogen-Ion Concentration; Isoquinolines - metabolism; Kinetics; Medical sciences; Molecular Sequence Data; Peptides - metabolism; Peptides - pharmacology; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Quinapril; Temperature; Tetrahydroisoquinolines; Time Factors
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1016247523311

To determine the transport mechanisms of quinapril and cephalexin in Caco-2 cell monolayers, a cell culture model of the human small intestinal epithelium. 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. 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). 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.