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

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Abstract
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 (β-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 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.