Competitive inhibition of glycylsarcosine transport by enalapril in rabbit renal brush border membrane vesicles: interaction of ACE inhibitors with high-affinity H+/peptide symporter.
OBJECTIVE
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 approximately 6 mM). Fosinopril and zofenopril had the greatest inhibitory potency (IC50 values of 55 and 81 microM, 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.
Lin
C J
CJ
College of Pharmacy and Upjohn Center for Clinical Pharmacology, The University of Michigan, Ann Arbor 48109, USA.
Akarawut
W
W
Smith
D E
DE
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002216:Captopril / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004151:Dipeptides / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000737:chemistry / Q000494:pharmacology*; D017328:Fosinopril / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D017706:Lisinopril / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D000074011:Peptide Transporter 1; D000077583:Quinapril; D011817:Rabbits; D017257:Ramipril / Q000737:chemistry / Q000494:pharmacology; D027981:Symporters; D044005:Tetrahydroisoquinolines
D000806:Angiotensin-Converting Enzyme Inhibitors; D002352:Carrier Proteins; D004151:Dipeptides; D007546:Isoquinolines; D008055:Lipids; D000074011:Peptide Transporter 1; D027981:Symporters; D044005:Tetrahydroisoquinolines; C044958:zofenopril; C004194:glycylsarcosine; C054501:quinaprilat; D004656:Enalapril; D002216:Captopril; D017706:Lisinopril; D017257:Ramipril; D017328:Fosinopril; D000077583:Quinapril