Competitive inhibition of glycylsarcosine transport by enalapril in rabbit renal brush border membrane vesicles: Interaction of ACE inhibitors with high-affinity H+/peptide symporter
Journal
Pharmaceutical Research
Journal Volume
16
Journal Issue
5
Pages
609-615
Date Issued
1999
Author(s)
Abstract
Purpose. To examine the inhibitory potential of enalapril [and other angiotensin converting enzyme (ACE) inhibitors] on glycylsarcosine (GlySar) transport by the high-affinity renal peptide transporter. Methods. Studies were performed in rabbit renal brush border membrane vesicles in which the uptake of radiolabeled GlySar was examined in the absence and presence of captopril, enalapril, enalaprilat, fosinopril, lisinopril, quinapril, quinaprilat, ramipril and zofenopril. Results. Kinetic analyses demonstrated that enalapril inhibited the uptake of GlySar in a competitive manner (Ki ≃ 6 mM). Fosinopril and zofenopril had the greatest inhibitory potency (IC50 values of 55 and 81 μM, respectively) while the other ACE inhibitors exhibited low-affinity interactions with the renal peptide transporter. With respect to structure-function, ACE inhibitor affinity was strongly correlated with drug lipophilicity (r = 0.944, p < 0.001 for all ACE inhibitors; r = 0.983, p < 0.001 without enalaprilat, quinaprilat and quinapril). Conclusions. The data suggest that enalapril and GlySar compete for the same substrate-binding site on the high-affinity peptide transporter in kidney, and that ACE inhibitors can interact with the renal carrier and inhibit dipeptide transport.
Type
journal article