Summary
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.
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Alberts AW, Chen J, Kuron G, Hunt V, Huff J, et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proceedings of the National Academy of Sciences of the USA 77: 3957–3961, 1980
Anderson RGW, Orci L, Brown MS, Garcia-Segura LM, Goldstein JL. Ultrastructural analysis of crystalloid endoplasmic reticulum in UT-1 cells and its disappearance in response to cholesterol. Journal of Cell Science 63: 1–20, 1983
Berry PH, MacDonald JS, Alberts AW, et al. Brain and optic system pathology in hypocholesterolemic dogs treated with a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. American Journal of Pathology 132: 427–443, 1988
Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 232: 34–47, 1986
Bucher NLR, Overath P, Lynen F. 3-Hydroxy-methylglutaryl coenzyme A reductase, cleavage and condensing enzymes in relation to cholesterol formation in rat liver. Biochimica et Biophysica Acta 40: 491–501, 1960
Chao YS, Kroon PA, Yamin TT, Thompson GM, Alberts AW. Regulation of hepatic receptor-dependent degradation of LDL by mevinolin in rabbits with hypercholesterolaemia induced by a wheat starch-casein diet. Biochimica et Biophysica Acta 754: 134–141, 1983
Cuthbert JA, East CA, Bilheimer DW, Lipsky PE. Detection of familial hypercholesterolaemia by assaying functional low-density lipoprotein receptors on lymphocytes. New England Journal of Medicine 314: 879–883, 1986
Endo A, Kuroda M, Tsujita Y. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinum. Journal of Antibiotics 29: 1346–1348, 1976
Germershausen JI, Hunt VM, Bostedor RG, Bailey PJ, Karkas JD, et al. Tissue selectivity of the cholesterol-lowering agents lovastatin, simvastatin, and pravastatin in rats in vivo (abstract). Federation of American Societies for Experimental Biology Journal 2: A1752, 1988
Goldstein JL, Brown MS. Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. Proceedings of the National Academy of Sciences of the USA 70: 2804–2808, 1973
Goldstein JL, Helgeson JAS, Brown MS. Inhibition of cholesterol synthesis with compactin renders growth of cultured cells dependent on the low density lipoprotein receptor. Journal of Biological Chemistry 254: 5403–5409, 1979
Gordon DT, Rifkind BM. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: a new class of cholesterol-lowering agents. Annals of Internal Medicine 107: 759–761, 1987
Gould RG. Lipid metabolism and atherosclerosis. American Journal of Medicine 11: 209–227, 1951
Haruyama H, Kuwano H, Kinoshita T, Terahara A, Nishigaki T, et al. Structure elucidation of the bioactive metabolites of ML-236B (Mevastatin) isolated from dog urine. Chemical and Pharmaceutical Bulletin 34: 1459–1467, 1986
Hoffman WF, Alberts AW, Anderson PS, Chen JS, Smith RL, et al. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 4. Sidechain ester derivatives of mevinolin. Journal of Medicinal Chemistry 29: 849–852, 1986
Kornbrust D, Peter CP, MacDonald JS. Mechanism-based toxicity of HMG-CoA reductase inhibitors in rabbits (abstract). Toxicologist 8: 66, 1988
Lipid Research Clinics Coronary Primary Prevention Trial results. Reduction in incidence of coronary heart disease. Lipid Research Clinics Program. Lipid Metabolism-Atherogenesis Branch. National Heart, Lung and Blood Institute. Journal of the American Medical Association 251: 351–364, 1984a
Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. Lipid Research Clinics Program. Lipid Metabolism-Atherogenesis Branch. National Heart, Lung and Blood Institute. Journal of the American Medical Association 251: 365–374, 1984b
Lovastatin Long Term Safety Study: Interim Report. 8th International Symposium on Atherosclerosis, abstract, in press
Rodwell VW, Nordstrom JL, Mitschelen JJ. Regulation of HMG-CoA reductase. Advances in Lipid Research 14: 1–74, 1976
Singer II, Kawka DW, Kazazis DM, Alberts AW, Chen JS, et al. Hydroxymethylglutaryl-coenzyme A reductase-containing hepatocytes are distributed periportally in normal and mevinolin-treated rat livers. Proceedings of the National Academy of Sciences of the USA 81: 5556–5560, 1984
Singer II, Kawka DW, McNally SE, Scott S, Alberts AW, et al. Hydroxymethylglutaryl-coenzyme A reductase exhibits graded distribution in normal and mevinolin-treated ileum. Arteriosclerosis 7: 144–151, 1987
Singer II, Scott S, Kazazis DM, Huff J. Mevacor, an inhibitor of cholesterol synthesis, induced hydroxymethylglutaryl-coenzyme A reductase directly on membranes of expanded smooth endoplasmic reticulum. Proceedings of the National Academy of Sciences of the USA 85: 5264–5268, 1988
Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. American Journal of Cardiology 62: 28J–34J, 1988
Tsujita Y, Kuroda M, Shimada Y, Tanzawak, Arai M, et al. CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibitor of steroid synthesis and hypolipidemic effects on various animal species. Biochimica et Biophysica Acta 877: 50–60. 1986
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Slater, E.E., MacDonald, J.S. Mechanism of Action and Biological Profile of HMG CoA Reductase Inhibitors. Drugs 36 (Suppl 3), 72–82 (1988). https://doi.org/10.2165/00003495-198800363-00016
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DOI: https://doi.org/10.2165/00003495-198800363-00016