A radioimmunoassay for SQ 27,519, the active phosphinic acid-carboxylic diacid of the prodrug fosinopril in human serum.
Fosinopril (SQ 28,555) is a member of a new chemical class of angiotensin converting enzyme inhibitors being developed by The Squibb Institute for Medical Research. During or following absorption, fosinopril, a prodrug, is hydrolyzed pharmacologically to the active diacid, SQ 27,519. A specific radioimmunoassay (RIA) for the measurement of SQ 27,519 in human serum has been developed. The assay utilizes a specific SQ 27,519 antibody, 125I-iodohistamine-SQ 27,519 radiolabel, and human serum standards. Satisfactory zero binding and assay sensitivity are achieved after a 2-h incubation at room temperature. Separation of the antibody-bound and free radiolabeled antigens is achieved by using polyethylene glycol-goat anti-rabbit gamma globulin separant. Recovery efficiencies ranged from 97.2 to 109.4%. The assay exhibited little or no cross-reactivity with captopril. Cross-reactivities for prodrug (SQ 28,555) and phenolic SQ 27,519 were 5 and 9%, respectively. Intra-assay variability (3.3-5.6%) and interassay variability (7.1-6.6%) were observed. Linear regression analysis indicates that RIA and [14C] thin-layer radiochromatography (TLRC) methods gave a highly significant correlation (RIA = 1.0 [14C]TLRC + 0.17, r = 0.991). Pharmacokinetic profiles of patient sera containing SQ 27,519 obtained by RIA and [14C]TLRC are identical. The RIA has been used routinely in support of the bioavailability and pharmacokinetic studies of fosinopril in humans.
Tu
J I
JI
Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903.
Brennan
J
J
Stouffer
B
B
Eckelman
W C
WC
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood*; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D002855:Chromatography, Thin Layer / Q000379:methods; D003429:Cross Reactions; D017328:Fosinopril / Q000031:analogs & derivatives; D006801:Humans; D007275:Injections, Intravenous; D009943:Organophosphorus Compounds / Q000097:blood*; D011355:Prodrugs / Q000378:metabolism*; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D011485:Protein Binding; D011817:Rabbits; D011863:Radioimmunoassay / Q000379:methods
D000806:Angiotensin-Converting Enzyme Inhibitors; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D009943:Organophosphorus Compounds; D011355:Prodrugs; D011392:Proline; D017328:Fosinopril; C046965:fosinoprilat