Angiotensin-converting enzyme (ACE) inhibitor transport in human intestinal epithelial (Caco-2) cells

Br J Pharmacol. 1995 Mar;114(5):981-6. doi: 10.1111/j.1476-5381.1995.tb13301.x.


1. The role of proton-linked solute transport in the absorption of the angiotensin-converting enzyme (ACE) inhibitors captopril, enalapril maleate and lisinopril has been investigated in human intestinal epithelial (Caco-2) cell monolayers. 2. In Caco-2 cell monolayers the transepithelial apical-to-basal transport and intracellular accumulation (across the apical membrane) of the hydrolysis-resistant dipeptide, glycylsarcosine (Gly-Sar), were stimulated by acidification (pH 6.0) of the apical environment. In contrast, transport and intracellular accumulation of the angiotensin-converting enzyme (ACE) inhibitor, lisinopril, were low (lower than the paracellular marker mannitol) and were not stimulated by apical acidification. Furthermore, [14C]-lisinopril transport showed little reduction when excess unlabelled lisinopril (20 mM) was added. 3. pH-dependent [14C]-Gly-Sar transport was inhibited by the orally-active ACE inhibitors, enalapril maleate and captopril (both at 20 mM). Lisinopril (20 mM) had a relatively small inhibitory effect on [14C]-Gly-Sar transport. pH-dependent [3H]-proline transport was not inhibited by captopril, enalapril maleate or lisinopril. 4. Experiments with BCECF[2',7',-bis(2-carboxyethyl)-5(6)-carboxyfluorescein]-loaded Caco-2 cells demonstrate that dipeptide transport across the apical membrane is associated with proton flow into the cell. The dipeptide, carnosine (beta-alanyl-L-histidine) and the ACE inhibitors enalapril maleate and captopril, all lowered intracellular pH when perfused at the apical surface of Caco-2 cell monolayers. However, lisinopril was without effect. 5. The effects of enalapril maleate and captopril on [14C]-Gly-Sar transport and pHi suggest that these two ACE inhibitors share the H(+)-coupled mechanism involved in dipeptide transport. The absence of pH-dependent [14C]-lisinopril transport, the relatively small inhibitory effect on [14C]-Gly-Sar transport,and the absence of lisinopril-induced pHi changes, all suggest that lisinopril is a poor substrate for thedi/tripeptide carrier in Caco-2 cells. These observations are consistent with the greater oral availability and time-dependent absorption profile of enalapril maleate and captopril, compared to lisinopril.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / metabolism*
  • Carnosine / metabolism
  • Carnosine / pharmacology
  • Cell Line
  • Dipeptides / metabolism
  • Dipeptides / pharmacology
  • Epithelial Cells
  • Epithelium / metabolism
  • Fluoresceins / metabolism
  • Fluoresceins / pharmacology
  • Fluorescent Dyes / metabolism
  • Fluorescent Dyes / pharmacology
  • Humans
  • Hydrogen-Ion Concentration
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / metabolism*


  • Angiotensin-Converting Enzyme Inhibitors
  • Dipeptides
  • Fluoresceins
  • Fluorescent Dyes
  • glycylsarcosine
  • 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein
  • Carnosine