Radioimmunoassays for a new angiotensin-converting enzyme inhibitor, zabicipril, and its active metabolite, zabiciprilat, in human plasma.
Zabicipril (Z), a new angiotensin-converting-enzyme inhibitor under development, is a prodrug that has to be deesterified in vivo to the active metabolite, zabiciprilat (ZT), to reach its antihypertensive pharmacological properties. Two radioimmunoassays have been developed for the measurement of both Z and ZT in human plasma. Anti-Z and anti-ZT antibodies were raised in rabbits against their respective lysine analogues conjugated to bovine serum albumin. [3H]Z and [3H]ZT were used as radioligands for the prodrug (Z) and the drug (ZT), respectively. Studies on anti-Z antiserum specificity showed no significant cross-reactivity (< 0.1%) with the active metabolite (ZT); similarly, Z is poorly recognized (0.5%) by the anti-ZT antiserum. Both antisera showed little cross-reaction (2%) with glucuronide metabolites. The sensitivities of the assays were 1 and 0.2 ng/mL for Z and ZT, respectively. Interassay coefficients of variation ranged from 9 to 12% for Z at 2-50 ng/mL and from 8 to 13% for ZT at 0.5-5 ng/mL. These assays were used to investigate the pharmacokinetic profile of both Z and its pharmacologically active metabolite ZT after intravenous infusion of Z in human volunteers.
Lelievre
E
E
Bio-Pharmacie Servier, Orléans, France.
Cardona
H
H
Brillanceau
M H
MH
Piraube
C
C
Sauveur
C
C
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000097:blood* / Q000493:pharmacokinetics; D000818:Animals; D000936:Antigen-Antibody Complex / Q000097:blood; D001643:Bridged Bicyclo Compounds / Q000097:blood* / Q000493:pharmacokinetics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003429:Cross Reactions; D005069:Evaluation Studies as Topic; D006801:Humans; D011817:Rabbits; D011863:Radioimmunoassay / Q000379:methods*; D011869:Radioligand Assay; D015203:Reproducibility of Results
D000806:Angiotensin-Converting Enzyme Inhibitors; D000936:Antigen-Antibody Complex; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; C067839:zabiciprilat; C065499:zabicipril