Quinapril—A Preclinical Review of the Pharmacology, Pharmacokinetics, and Toxicology

Abstract

Quinapril is an orally active, non- peptide, nonsulfhydryl angiotensin- converting enzyme (ACE) inhibitor that acts potently and specifically to interrupt the conversion of angioten sin I to angiotensin II in both plasma and tissue. Quinapril is enzymatically hydrolyzed to a pharmacologically active diacid form quinaprilat. Quinapril is efficacious in hyperten sive models exhibiting both high (re nal hypertensive rats, diuretic- treated dogs) and normal (spontan eously hypertensive rats) plasma re nin activity. Quinapril does not pre vent the development of hypertension when plasma renin activity (PRA) is markedly suppressed as in the deoxy corticosterone-saline treated rat. He modynamic studies in dogs indicate that quinapril decreases total periph eral and renal vascular resistance. Quinaprilat produces natriuresis and mild diuresis at doses that do not al ter mean arterial blood pressure. Quinapril has the potential to affect plasma lipids beneficially or at least be "lipid neutral." Oral absorption of quinapril is rapid in rats, dogs, and monkeys. There is rapid and exten sive distribution of radiolabel to most tissues except brain. Plasma radiola bel concentration-time profiles ex hibit polyexponential decay with a prolonged terminal phase at low con centrations in all species. Metabolism to compounds other than quinaprilat is not extensive. Quinapril is excreted primarily as quinaprilat and to a lesser degree as quinapril. Quinapril is well tolerated in a variety of phar macologic safety screens and its tox icity profile is similar to that of other ACE inhibitors. Quinapril does not adversely affect reproduction; it is not teratogenic, carcinogenic, or mu tagenic. Preclinical studies indicate that quinapril is a safe and effective ACE inhibitor and that its activity re sides mainly in the diacid form (quinaprilat). The reduction in per ipheral vascular resistance associated with plasma and tissue ACE inhibi tion most likely accounts for the ther apeutic benefit of quinapril in hyper tension and congestive heart failure in man.