ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITOR TRANSPORT IN HUMAN INTESTINAL EPITHELIAL (CACO-2) CELLS

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, [C-14]-lisinopril transport showed little reduction when excess unlabelled lisinopril (20 mM) was added. 3 pH-dependent [C-14]-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 [C-14]-Gly-Sar transport. pH-dependent [H-3]-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 [C-14]-Gly-Sar transport and pH(i) suggest that these two ACE inhibitors share the H+-coupled mechanism involved in dipeptide transport. The absence of pH-dependent [C-14]-lisinopril transport, the relatively small inhibitory effect on [C-14]-Gly-Sar transport, and the absence of lisinopril-induced pH(i) changes, all suggest that lisinopril is a poor substrate for the; di/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.