Disposition of [14C]-benazepril hydrochloride in rat, dog and baboon. Absorption, distribution, kinetics, biotransformation and excretion.
The compound 3-[(1-ethoxycarbonyl-3-phenyl-(1S)-propyl)-amino]-2,3,4,5- tetrahydro-2-oxo-1-(3S)-benzazepine-1-acetic acid hydrochloride (benazepril.HCl, CGS 14 824 A) is an ethyl ester prodrug of the angiotensin converting enzyme (ACE) inhibitor benazeprilat (CGS 14 831). The disposition of both compounds was studied in rat, dog and baboon after peroral and intravenous dosing of 14C-labelled preparations (2.5-3 mg/kg). Perorally dosed benazeprilat was poorly absorbed in rats, whereas benazepril.HCl was well absorbed in all species. Onset of absorption of benazepril.HCl was fast. Plasma concentrations of radioactivity indicated a prolonged absorption process. Upon intravenous benazepril.HCl, plasma levels declined rapidly in all species but showed a slow terminal elimination phase. Distribution to all organs and tissues occurred rapidly and was typical for an acid compound. Passage of the blood-brain barrier and of the placenta occurred to a minimal extent. No accumulation was observed after repeated dose. Radioactivity was rapidly and completely eliminated; biliary excretion was important. In the rat, benazepril was completely hydrolysed by first pass metabolism to the pharmacologically active benazeprilat. In dog and baboon hydrolysis was incomplete and additional hydrophilic metabolites were formed also.
Waldmeier
F
F
Ciba-Geigy Limited, Research and Development Department, Pharmaceuticals Division, Basle, Switzerland.
Schmid
K
K
D000818:Animals; D001552:Benzazepines / Q000378:metabolism / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004950:Esterases / Q000097:blood; D005243:Feces / Q000032:analysis; D007408:Intestinal Absorption; D008297:Male; D010215:Papio; D011485:Protein Binding; D051381:Rats; D013045:Species Specificity; D014018:Tissue Distribution
D001552:Benzazepines; D001798:Blood Proteins; D004950:Esterases; C052133:benazeprilat