Mechanism of action and biological profile of HMG CoA reductase inhibitors. A new therapeutic alternative.
Lovastatin (MK-803, mevinolin) and simvastatin (MK-733, synvinolin), 2 highly potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, have been heralded as breakthrough therapy for the treatment of atherosclerotic disease. This paper discusses the biochemical attributes of these HMG CoA reductase inhibitors, their structures and inhibitory properties in a variety of biological systems and presents the rationale for their therapeutic use. Not only do lovastatin and simvastatin potently inhibit cholesterol biosynthesis; they also can result in the induction of hepatic low density lipoprotein (LDL) receptors, thus increasing the catabolism of LDL-cholesterol. Lovastatin and simvastatin are the first HMG CoA reductase inhibitors to receive regulatory agency approval for marketed use. Their safety profiles are reviewed and 2 aspects of this evaluation are stressed. First, the objective in the clinical use of these inhibitors is to normalise plasma cholesterol levels in hypercholesterolaemic individuals. This contrasts with the profound reductions in cholesterol obtained when normocholesterolaemic animals are treated by the high doses of these drugs required for toxicological assessment. Second, both lovastatin and simvastatin are administered as prodrugs in their lactone forms. As lactones, they readily undergo first-pass metabolism, hepatic sequestration and hydrolysis to the active form. Consequently, lovastatin and simvastatin achieve lower plasma drug levels than do other HMG CoA reductase inhibitors in clinical development. Low plasma levels have been established as an important determinant of safety in the use of HMG CoA reductase inhibitors in both animal and human studies.
Slater
E E
EE
Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey.
MacDonald
J S
JS
D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000188:drug therapy*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives / Q000627:therapeutic use; D019821:Simvastatin
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019821:Simvastatin