Lovastatin was patented in 1979 and approved for medical use in 1987. It is available as a generic medication. In the United States the wholesale cost is about 0.05 USD per dose. In 2016 it was the 72nd most prescribed medication in the United States with more than 11 million prescriptions. Lovastatin was not available in the United Kingdom as of 2009.
The primary uses of lovastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease. It is recommended to be used only after other measures, such as diet, exercise, and weight reduction, have not improved cholesterol levels.
Lovastatin is usually well tolerated, with the most common side effects being, in approximately descending order of frequency: creatine phosphokinase elevation, flatulence, abdominal pain, constipation, diarrhoea, muscle aches or pains, nausea, indigestion, weakness, blurred vision, rash, dizziness and muscle cramps. As with all statin drugs, it can rarely cause myopathy, hepatotoxicity (liver damage), dermatomyositis or rhabdomyolysis. This can be life-threatening if not recognised and treated in time, so any unexplained muscle pain or weakness whilst on lovastatin should be promptly mentioned to the prescribing doctor. Other uncommon side effects that should be promptly mentioned to either the prescribing doctor or an emergency medical service include:
swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
These less serious side effects should still be reported if they persist or increase in severity:
memory loss or forgetfulness
Contraindications, conditions that warrant withholding treatment with lovastatin, include pregnancy, breast feeding, and liver disease. Lovastatin is contraindicated during pregnancy (Pregnancy Category X); it may cause birth defects such as skeletal deformities or learning disabilities. Due to its potential to disrupt infant lipid metabolism, lovastatin should not be taken while breastfeeding. Patients with liver disease should not take lovastatin.
As with atorvastatin, simvastatin, and other statin drugs metabolized via CYP3A4, drinking grapefruit juice during lovastatin therapy may increase the risk of side effects. Components of grapefruit juice, the flavonoidnaringin, or the furanocoumarinbergamottin inhibit CYP3A4 in vitro, and may account for the in vivo effect of grapefruit juice concentrate decreasing the metabolic clearance of lovastatin, and increasing its plasma concentrations.
Mechanism of action
Lovastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme that catalyzes the conversion of HMG-CoA to mevalonate.
Mevalonate is a required building block for cholesterol biosynthesis and lovastatin interferes with its production by acting as a reversible competitive inhibitor for HMG-CoA, which binds to the HMG-CoA reductase. Lovastatin is a prodrug, an inactive lactone in its native form, the gamma-lactone closed ring form in which it is administered, is hydrolysed in vivo to the β-hydroxy acid open ring form; which is the active form.
Lovastatin and other statins have been studied for their chemopreventive and chemotherapeutic effects. No such effects were seen in the early studies. More recent investigations revealed some chemopreventive and therapeutic effects, for certain types of cancer, especially in combination of statins with other anticancer drugs. It is likely that these effect are mediated by the properties of statins to reduce proteasome activity, leading to an accumulation of cyclin-dependent kinase inhibitors p21 and p27, and to subsequent G1-phase arrest, as seen in cells of different cancer lines.
Compactin and lovastatin, natural products with a powerful inhibitory effect on HMG-CoA reductase, were discovered in the 1970s, and taken into clinical development as potential drugs for lowering LDL cholesterol.
In 1982, some small-scale clinical investigations of lovastatin, a polyketide-derived natural product isolated from Aspergillus terreus, in very high-risk patients were undertaken, in which dramatic reductions in LDL cholesterol were observed, with very few adverse effects. After the additional animal safety studies with lovastatin revealed no toxicity of the type thought to be associated with compactin, clinical studies continued.
Large-scale trials confirmed the effectiveness of lovastatin. Observed tolerability continued to be excellent, and lovastatin was approved by the US FDA in 1987. It was the first statin approved by the FDA.
The objective is to decrease excess levels of cholesterol to an amount consistent with maintenance of normal body function. Cholesterol is biosynthesized in a series of more than 25 separate enzymatic reactions that initially involves three successive condensations of acetyl-CoA units to form the six-carbon compound 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA). This is reduced to mevalonate and then converted in a series of reactions to the isoprenes that are building-blocks of squalene, the immediate precursor to sterols, which cyclizes to lanosterol (a methylated sterol) and further metabolized to cholesterol. A number of early attempts to block the synthesis of cholesterol resulted in agents that inhibited late in the biosynthetic pathway between lanosterol and cholesterol. A major rate-limiting step in the pathway is at the level of the microsomal enzyme that catalyzes the conversion of HMG CoA to mevalonic acid, and that has been considered to be a prime target for pharmacologic intervention for several years.
HMG CoA reductase occurs early in the biosynthetic pathway and is among the first committed steps to cholesterol formulation. Inhibition of this enzyme could lead to accumulation of HMG CoA, a water-soluble intermediate that is, then, capable of being readily metabolized to simpler molecules. This inhibition of reductase would lead to accumulation of lipophylic intermediates with a formal sterol ring.
Lovastatin was the first specific inhibitor of HMG CoA reductase to receive approval for the treatment of hypercholesterolemia. The first breakthrough in efforts to find a potent, specific, competitive inhibitor of HMG CoA reductase occurred in 1976, when Endoet al. reported the discovery of mevastatin, a highly functionalized fungal metabolite, isolated from cultures of Penicillium citrium.
In vitro formation of a triketide lactone using a genetically modified protein derived from 6-deoxyerythronolide B synthase has been demonstrated. Witter and Vederas observed, "the stereochemistry of the molecule supports the intriguing idea that an enzyme-catalyzed Diels-Alder reaction may occur during assembly of the polyketide chain. It, thus, appears that biological Diels-Alder reactions may be triggered by generation of reactive triene systems on an enzyme surface."
A major bulk of work in the synthesis of lovastatin was done by M. Hirama in the 1980s.
Hirama synthesized compactin and used one of the intermediates to follow a different path to get to lovastatin. The synthetic sequence is shown in the schemes below. The γ-lactone was synthesized using Yamada methodology starting with glutamic acid. Lactone opening was done using lithium methoxide in methanol and then silylation to give a separable mixture of the starting lactone and the silyl ether. The silyl ether on hydrogenolysis followed by Collins oxidation gave the aldehyde. Stereoselective preparation of (E,E)-diene was accomplished by addition of trans-crotyl phenyl sulfone anion, followed by quenching with Ac2O and subsequent reductive elimination of sulfone acetate. Condensation of this with lithium anion of dimethyl methylphosphonate gave compound 1. Compound 2 was synthesized as shown in the scheme in the synthetic procedure. Compounds 1 and 2 were then combined together using 1.3 eq sodium hydride in THF followed by reflux in chlorobenzene for 82 hr under nitrogen to get the enone 3.
Simple organic reactions were used to get to lovastatin as shown in the scheme.
Cholesterol biosynthetic pathway
HMG CoA reductase reaction
Biosynthesis using Diels-Alder catalyzed cyclization
Biosynthesis using broadly specific acyltransferase
^Katz MS (2005). "Therapy insight: Potential of statins for cancer chemoprevention and therapy". Nature Clinical Practice Oncology. 2 (2): 82–9. doi:10.1038/ncponc0097. PMID16264880.
^Chae YK, Yousaf M, Malecek MK, Carneiro B, Chandra S, Kaplan J, Kalyan A, Sassano A, Platanias LC, Giles F. (2015) Statins as anti-cancer therapy; Can we translate preclinical and epidemiologic data into clinical benefit? Discov Med. Dec;20(112):413-27. PMID26760985.
^Jakóbisiak M, Bruno S, Skierski J, Darzynkiewicz Z. (1991) The cell cycle specific effects of lovastatin. Proc Natl Acad Sci USA 88:3628-3632. PMID1673788PMC51505
^Alarcón J, Aguila S, Arancibia-Avila P, Fuentes O, Zamorano-Ponce E, Hernández M (Jan–Feb 2003). "Production and purification of statins from Pleurotus ostreatus (Basidiomycetes) strains". Z Naturforsch C. 58 (1–2): 62–4. doi:10.1515/znc-2003-1-211. PMID12622228.
^Vederas JC, Moore RN, Bigam G, Chan KJ (1985). "Biosynthesis of the hypocholesterolemic agent mevinolin by Aspergillus terreus. Determination of the origin of carbon, hydrogen and oxygen by 13C NMR and mass spectrometry". J Am Chem Soc. 107 (12): 3694–701. doi:10.1021/ja00298a046.
^Opletal L, Jahodár L, Chobot V, et al. (December 1997). "Evidence for the anti-hyperlipidaemic activity of the edible fungus Pleurotus ostreatus". Br. J. Biomed. Sci. 54 (4): 240–3. PMID9624732.
^Bajaj M, Vadhera S, Brar AP, Soni GL (October 1997). "Role of oyster mushroom (Pleurotus florida) as hypocholesterolemic/antiatherogenic agent". Indian J. Exp. Biol. 35 (10): 1070–5. PMID9475042.
^Bobek P, Ozdín L, Kuniak L, Hromadová M (March 1997). "[Regulation of cholesterol metabolism with dietary addition of oyster mushrooms (Pleurotus ostreatus) in rats with hypercholesterolemia]". Cas. Lek. Cesk. (in Slovak). 136 (6): 186–90. PMID9221192.
^Bobek P, Ozdín L, Kuniak L (August 1996). "Effect of oyster mushroom (Pleurotus Ostreatus) and its ethanolic extract in diet on absorption and turnover of cholesterol in hypercholesterolemic rat". Nahrung. 40 (4): 222–4. doi:10.1002/food.19960400413. PMID8810086.
^Bobek P, Ozdín O, Mikus M (1995). "Dietary oyster mushroom (Pleurotus ostreatus) accelerates plasma cholesterol turnover in hypercholesterolaemic rat". Physiol Res. 44 (5): 287–91. PMID8869262.
^Bobek P, Ozdin L, Kuniak L (1995). "The effect of oyster mushroom (Pleurotus ostreatus), its ethanolic extract and extraction residues on cholesterol levels in serum, lipoproteins and liver of rat". Nahrung. 39 (1): 98–9. doi:10.1002/food.19950390113. PMID7898579.
^Bobek P, Ozdin L, Kuniak L (March 1994). "Mechanism of hypocholesterolemic effect of oyster mushroom (Pleurotus ostreatus) in rats: reduction of cholesterol absorption and increase of plasma cholesterol removal". Z Ernahrungswiss. 33 (1): 44–50. doi:10.1007/BF01610577. PMID8197787.
^Chorváthová V, Bobek P, Ginter E, Klvanová J (1993). "Effect of the oyster fungus on glycaemia and cholesterolaemia in rats with insulin-dependent diabetes". Physiol Res. 42 (3): 175–9. PMID8218150.
^Bobek P, Ginter E, Jurcovicová M, Kuniak L (1991). "Cholesterol-lowering effect of the mushroom Pleurotus ostreatus in hereditary hypercholesterolemic rats". Ann. Nutr. Metab. 35 (4): 191–5. doi:10.1159/000177644. PMID1897899.
^Khatun K, Mahtab H, Khanam PA, Sayeed MA, Khan KA (January 2007). "Oyster mushroom reduced blood glucose and cholesterol in diabetic subjects". Mymensingh Med J. 16 (1): 94–9. doi:10.3329/mmj.v16i1.261. PMID17344789.
^"FDA bans red yeast rice product" by Michael McCarthy, The Lancet, Volume 351, Issue 9116, Page 1637, 30 May 1998
^Endo, Akira; Kuroda M.; Tsujita Y. (December 1976). "ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium". Journal of Antibiotics (Tokyo). 29 (12): 1346–8. doi:10.7164/antibiotics.29.1346. PMID1010803.
^Hirama M, Vet M (1982). "A chiral total synthesis of compactin". J. Am. Chem. Soc. 104 (15): 4251. doi:10.1021/ja00379a037.
^Hirama M, Iwashita; Iwashita, Mitsuko (1983). "Synthesis of (+)-Mevinolin starting from Naturally occurring building blocks and using an asymmetry inducing reaction". Tetrahedron Lett. 24 (17): 1811–1812. doi:10.1016/S0040-4039(00)81777-3.
^Gunde-Cimerman, N; Cimerman, A (March 1995). "Pleurotus fruiting bodies contain the inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase-lovastatin". Experimental Mycology. 19 (1): 1–6. doi:10.1006/emyc.1995.1001. PMID7614366.