Disposition of Zofenopril Calcium in Healthy Subjects

Zofenopril calcium (1) is a prodrug that is hydrolyzed in vivo to the active angiotensin-converting enzyme (ACE) inhibitor SQ 26,333 (2). In a two-way crossover study, six healthy male subjects (age range 25–36 years) each received an iv 11.2-mg dose of [14C]SQ 26,703 (14C-3; the L-arginine salt of...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 1990-11, Vol.79 (11), p.970-973
Main Authors: Singhvi, Sampat M., Foley, James E., Willard, David A., Morrison, Richard A.
Format: Article
Language:English
Subjects:
Administration, Oral
Adult
Angiotensin-Converting Enzyme Inhibitors - administration & dosage
Angiotensin-Converting Enzyme Inhibitors - pharmacokinetics
Antihypertensive agents
Biological and medical sciences
Biological Availability
Biotransformation
Blood Proteins - metabolism
Captopril - administration & dosage
Captopril - analogs & derivatives
Captopril - pharmacokinetics
Cardiovascular system
Chromatography, Thin Layer
Ethylmaleimide - metabolism
Feces - chemistry
Half-Life
Humans
Injections, Intravenous
Male
Medical sciences
Pharmacology. Drug treatments
Protein Binding
Random Allocation
Reference Values
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Summary:Zofenopril calcium (1) is a prodrug that is hydrolyzed in vivo to the active angiotensin-converting enzyme (ACE) inhibitor SQ 26,333 (2). In a two-way crossover study, six healthy male subjects (age range 25–36 years) each received an iv 11.2-mg dose of [14C]SQ 26,703 (14C-3; the L-arginine salt of 2) and an oral 10-mg (equimolar) dose of 14C-1. After the iv dose of 14C-3, the 0–96-h recovery of radioactivity averaged 76 and 16% of the dose in urine and feces, respectively, indicating substantial biliary secretion. After the oral dose of 14C-1, excretion of radioactivity averaged 70% (urine) and 26% (feces). Negligible amounts of 1 were present in urine, indicating complete hydrolysis of the orally administered prodrug. The oral absorption of 1 was almost complete and the oral bioavailability of 2 averaged ~70%. The terminal elimination half-life for 2 after the iv dose averaged 5.5h. Whole body clearance, renal clearance, nonrenal clearance, and Vdss averaged 11.4, 3.1, and 8.3 mL/min/kg and 1.3 L/kg, respectively. These data indicated that 2 is eliminated by the kidney as well as the liver, is extensively metabolized, and is distributed extensively into extravascular sites.
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.2600791105