title: Specific and high affinity binding of perindoprilat, but not of perindopril to blood ACE.
abstract: The bindings of perindopril and of its active metabolite perindoprilat to human serum, isolated proteins and to erythrocytes were studied by equilibrium dialysis. Within the therapeutic concentrations range, perindopril was 74% bound to serum involving a non-saturable process, NKa = 2.87. The main binders are serum albumin and alpha 1-acid glycoprotein. The serum binding of perindoprilat involved two successive steps. First, a saturable high-affinity binding (Ka: 2.8 x 10(9) M-1) occurred, involving probably the angiotensin converting enzyme (ACE). The second binding step was non-saturable with a very weak binding capacity, NKa = 0.15, quite superimposable to the HSA bound perindoprilat. Free fatty acids (FFA) did not alter the binding to HSA. The binding of both compounds to erythrocytes was low especially with perindopril, when measured in the presence of plasma. A significant correlation showed that the overall serum binding percentage of both drugs was essentially determined by HSA concentration. Serum binding was decreased in renal failure or cirrhosis, this result was principally linked to the hypoalbuminemia. Interactions with other drugs were limited to the binding of salicylate, tolbutamide and digitoxin to HSA.
authors.affiliation: Département de Pharmacologie, Faculté de Médecine, Paris XII, Créteil, France.
authors.forename: F
authors.initials: F
authors.lastname: Bree
authors.forename: P
authors.initials: P
authors.lastname: Nguyen
authors.forename: S
authors.initials: S
authors.lastname: Urien
authors.forename: G
authors.initials: G
authors.lastname: Resplandy
authors.forename: J P
authors.initials: JP
authors.lastname: Tillement
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood*; D001798:Blood Proteins / Q000378:metabolism; D004347:Drug Interactions; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000097:blood*; D007700:Kinetics; D017093:Liver Failure / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000097:blood*; D020913:Perindopril; D011485:Protein Binding; D051437:Renal Insufficiency / Q000097:blood; D012680:Sensitivity and Specificity; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001798:Blood Proteins; D007211:Indoles; D012709:Serum Albumin; C053500:perindoprilat; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril