Mechanisms of Transport of Quinapril in Caco-2 Cell Monolayers: Comparison with Cephalexin

Ming Hu, Lixing Zheng, Jiyue Chen, Lijuan Liu, Yanping Zhu, Anne H. Dantzig, Robert Stratford Jr.

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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) 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 µg/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.

Original languageEnglish (US)
Pages (from-to)1120-1125
Number of pages6
JournalPharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists
Volume12
Issue number8
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

Fingerprint

Cephalexin
Caco-2 Cells
Monolayers
loracarbef
Protons
Enalapril
glycylproline
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Staurosporine
Amiloride
Intestinal Mucosa
Cell culture
Pharmaceutical Preparations
quinapril
Cell Culture Techniques
Maintenance
Temperature

Keywords

  • ACE inhibitor
  • Caco-2
  • cephalexin
  • intestinal absorption
  • oral β-lactam antibiotic
  • peptide carrier system
  • proton-gradient
  • quinapril

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

Cite this

Mechanisms of Transport of Quinapril in Caco-2 Cell Monolayers : Comparison with Cephalexin. / Hu, Ming; Zheng, Lixing; Chen, Jiyue; Liu, Lijuan; Zhu, Yanping; Dantzig, Anne H.; Stratford Jr., Robert.

In: Pharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists, Vol. 12, No. 8, 01.01.1995, p. 1120-1125.

Research output: Contribution to journalArticle

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title = "Mechanisms of Transport of Quinapril in Caco-2 Cell Monolayers: Comparison with Cephalexin",
abstract = "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) 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 µg/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.",
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author = "Ming Hu and Lixing Zheng and Jiyue Chen and Lijuan Liu and Yanping Zhu and Dantzig, {Anne H.} and {Stratford Jr.}, Robert",
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T1 - Mechanisms of Transport of Quinapril in Caco-2 Cell Monolayers

T2 - Comparison with Cephalexin

AU - Hu, Ming

AU - Zheng, Lixing

AU - Chen, Jiyue

AU - Liu, Lijuan

AU - Zhu, Yanping

AU - Dantzig, Anne H.

AU - Stratford Jr., Robert

PY - 1995/1/1

Y1 - 1995/1/1

N2 - 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) 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 µg/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.

AB - 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) 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 µg/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.

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KW - Caco-2

KW - cephalexin

KW - intestinal absorption

KW - oral β-lactam antibiotic

KW - peptide carrier system

KW - proton-gradient

KW - quinapril

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