The toxicology of HMG-CoA reductase inhibitors: prediction of human risk.
The discovery that 3-hydroxy-3-methyglutaryl coenzyme A reductase was a rate-determining step in the biosynthesis of cholesterol led to the discovery of inhibitors of this enzyme. To support the development of these agents (statins) as potential hypocholesterolemic drugs, a variety of preclinical studies were conducted in several animal species. Not unexpectedly due to the central role played by mevalonic acid and its products including cholesterol in development and maintenance of cellular homeostasis, administration of high dosage levels of these agents led to the expression of a broad variety of adverse effects in many different tissues. Using the tools of toxicologic pathology and classical risk assessment, these varied toxicities were evaluated by many groups relative to the conditions of use in human therapy and a perspective was developed on potential human risk. These approaches of mechanism-based risk assessment predicted that most of the adverse effects observed in animals would not be seen under conditions of human use and supported the successful introduction of one of the most important classes of human medicines.
MacDonald
James S
JS
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. james.macdonald@spcorp.com
Halleck
Margaretann M
MM
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000633:toxicity*; D006937:Hypercholesterolemia / Q000188:drug therapy; D008954:Models, Biological; D015394:Molecular Structure; D011237:Predictive Value of Tests; D018570:Risk Assessment / Q000379:methods*
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors