Lovastatin, sold under the brand name Mevacor among others, is a

statin medication Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low ...

, to treat high blood cholesterol and reduce the risk of

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...

. Its use is recommended together with lifestyle changes. It is taken by mouth. Common side effects include diarrhea, constipation, headache, muscles pains, rash, and trouble sleeping. Serious side effects may include

liver problems Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the s ...

, muscle breakdown, and

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

. Use during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

may harm the baby and use during

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...

is not recommended. It works by decreasing the liver's ability to produce cholesterol by blocking the enzyme

HMG-CoA reductase HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-controlling enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and ot ...

. Lovastatin was patented in 1979 and approved for medical use in 1987. It is on the World Health Organization's List of Essential Medicines. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ...

. In 2020, it was the 99th most commonly prescribed medication in the United States, with more than 7million prescriptions.

Medical uses

The primary uses of lovastatin is for the treatment of

dyslipidemia Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease ( ASCVD). ASCVD includes coronary ar ...

and the prevention of

. It is recommended to be used only after other measures, such as diet, exercise, and weight reduction, have not improved cholesterol levels.

Side effects

Lovastatin is usually well tolerated, with the most common side effects being, in approximately descending order of frequency: creatine phosphokinase elevation,

flatulence Flatulence, in humans, is the expulsion of gas from the intestines via the anus, commonly referred to as farting. "Flatus" is the medical word for gas generated in the stomach or bowels. A proportion of intestinal gas may be swallowed enviro ...

, abdominal pain, constipation,

diarrhoea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

, muscle aches or pains, nausea,

indigestion Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier t ...

, weakness, blurred vision, rash, dizziness and muscle cramps. As with all statin drugs, it can rarely cause

myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This me ...

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...

(liver damage),

dermatomyositis Dermatomyositis (DM) is a long-term inflammatory disorder which affects skin and the muscles. Its symptoms are generally a skin rash and worsening muscle weakness over time. These may occur suddenly or develop over months. Other symptoms may inc ...

rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of ...

. 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: These less serious side effects should still be reported if they persist or increase in severity:

Contraindications

Contraindication In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...

s, 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. Owing to its potential to disrupt infant lipid metabolism, lovastatin should not be taken while breastfeeding. Patients with liver disease should not take lovastatin.

Interactions

As with

atorvastatin Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth. Common ...

simvastatin Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of hear ...

, and other statin drugs metabolized via

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...

, drinking

grapefruit The grapefruit (''Citrus'' × ''paradisi'') is a subtropical citrus tree known for its relatively large, sour to semi-sweet, somewhat bitter fruit. The interior flesh is segmented and varies in color from pale yellow to dark pink. Grapefruit ...

juice during lovastatin therapy may increase the risk of side effects. Components of grapefruit juice, the

flavonoid Flavonoids (or bioflavonoids; from the Latin word ''flavus'', meaning yellow, their color in nature) are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans. Chemically, flavonoids ...

naringin Naringin is a flavanone-7-''O''- glycoside between the flavanone naringenin and the disaccharide neohesperidose. The flavonoid naringin occurs naturally in citrus fruits, especially in grapefruit, where naringin is responsible for the fruit's ...

, or the

furanocoumarin The furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. Most of the plant species found to contain furanocoumarins belong to a handful of plant families. The families Apiaceae and Rutace ...

bergamottin Bergamottin (5-geranoxypsoralen) is a natural furanocoumarin found in the pulp of pomelos and grapefruits. It is also found in the peel and pulp of the bergamot orange, from which it was first isolated and from which its name is derived. Chemis ...

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 A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...

, 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 Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

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 Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by whi ...

activity, leading to an accumulation of

cyclin-dependent kinase Cyclin-dependent kinases (CDKs) are the families of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. They ...

inhibitors p21 and p27, and to subsequent G₁-phase arrest, as seen in cells of different cancer lines.

History

Compactin Mevastatin (compactin, ML-236B) is a hypolipidemic agent that belongs to the statins class. It was isolated from the mold ''Penicillium citrinum'' by Akira Endo in the 1970s, and he identified it as a HMG-CoA reductase inhibitor, i.e., a statin ...

and lovastatin, natural products with a powerful inhibitory effect on

, 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. Lovastatin is also naturally produced by certain higher

fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately fr ...

, such as '' Pleurotus ostreatus'' (oyster mushroom) and closely related '' Pleurotus'' spp. Research into the effect of oyster mushroom and its extracts on the cholesterol levels of laboratory animals has been extensive, although the effect has been demonstrated in a very limited number of human subjects. In 1998, the FDA placed a ban on the sale of dietary supplements derived from red yeast rice, which naturally contains lovastatin, arguing that products containing prescription agents require drug approval. Judge Dale A. Kimball of the

United States District Court for the District of Utah The United States District Court for the District of Utah (in case citations, D. Utah) is the federal district court whose jurisdiction is the state of Utah. The court is based in Salt Lake City with another courtroom leased in thstate courth ...

, granted a motion by Cholestin's manufacturer, Pharmanex, that the agency's ban was illegal under the 1994 Dietary Supplement Health and Education Act because the product was marketed as a dietary supplement, not a drug. 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

isoprene Isoprene, or 2-methyl-1,3-butadiene, is a common volatile organic compound with the formula CH2=C(CH3)−CH=CH2. In its pure form it is a colorless volatile liquid. Isoprene is an unsaturated hydrocarbon. It is produced by many plants and animals ...

s 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 Endo ''et al.'' reported the discovery of

mevastatin Mevastatin (compactin, ML-236B) is a hypolipidemic agent that belongs to the statins class. It was isolated from the mold ''Penicillium citrinum'' by Akira Endo in the 1970s, and he identified it as a HMG-CoA reductase inhibitor, i.e., a statin. ...

, a highly functionalized fungal metabolite, isolated from cultures of ''Penicillium citrium''.

Biosynthesis

The biosynthesis of lovastatin occurs via an iterative type I polyketide synthase (PKS) pathway. The six genes that encode enzymes that are essential for the biosynthesis of lovastatin are lovB, lovC, lovA, lovD, lovG, and lovF . The synthesis of dihydromonacolin L requires a total of 9-malonyl Coa . It proceeds in the PKS pathway until it reaches (E) a hexaketide, where it undergoes a Diels-Alder cycloaddition to form the fused rings. After cyclization it continues through the PKS pathway until it reaches (I) a nonaketide, which then undergoes release from LovB through the thioesterase encoded by LovG. Dihydromonacolin L, (J), then undergoes oxidation and dehydration via a cytochrome P450 oxygenase encoded by LovA to obtain monacolin J, (L). The MT domain from lovB is active in the conversion of (B) to (C) when it transfers a methyl group from S-adenosyl-L-methionine (SAM) to the tetraketide (C) . Owing to the fact that LovB contains an inactive ER domain, LovC is required at specific steps to obtain fully reduced products. The domain organization of LovB, LovC, LovG and LovF is shown in Figure 2. The inactive ER domain of lovB is shown with an oval and where LovC acts in trans to LovB is shown with a red box. In a parallel pathway, the diketide side chain of lovastatin is synthesized by another highly reducing type I polyketide synthase enzyme encoded by LovF . Lastly, the side chain, 2-methylbutyrate (M) is covalently attached to C-8 hydroxy group of monacolin J (L) by a transesterase encoded by LovD to form lovastatin.

Total synthesis

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 Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...

and then

silylation Silylation is the introduction of one or more (usually) substituted silyl groups (R3Si) to a molecule. The process is the basis of organosilicon chemistry. Of organic compounds Alcohols, carboxylic acids, amines, thiols, and phosphates can be sil ...

to give a separable mixture of the starting lactone and the

silyl ether Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting ...

. 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 using 1.3 eq sodium hydride in THF followed by reflux in

chlorobenzene Chlorobenzene is an aromatic organic compound with the chemical formula C6H5Cl. This colorless, flammable liquid is a common solvent and a widely used intermediate in the manufacture of other chemicals. Uses Historical The major use of chlorob ...

for 82 hr under nitrogen to get the enone 3. Simple organic reactions were used to get to lovastatin as shown in the scheme. Image:Cholesterolbiosynthesis.png, Cholesterol biosynthetic pathway Image:Hmg-reductase.png, HMG CoA reductase reaction Image:Biosynthesis-dielsalder.png, Biosynthesis using Diels-Alder catalyzed cyclization Image:Biosynthesis-lovd.png, Biosynthesis using broadly specific acyltransferase Image:Totalsynthesis1.png, Synthesis of compounds 1 and 2 Image:Totalsynthesis2.png, Complete lovastatin synthesis

Society and culture

Natural sources

Lovastatin is a naturally occurring compound found in low concentrations in food such as oyster mushrooms, red yeast rice, and Pu-erh.

Brand names

Mevacor, Advicor (as a combination with

niacin Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. It can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a variet ...

), Altocor, Altoprev

Other applications

In plant physiology, lovastatin has occasionally been used as inhibitor of

cytokinin Cytokinins (CK) are a class of plant hormones that promote cell division, or cytokinesis, in plant roots and shoots. They are involved primarily in cell growth and differentiation, but also affect apical dominance, axillary bud growth, and lea ...

biosynthesis.

References

External links

* {{Portal bar , Medicine Wikipedia medicine articles ready to translate Statins Carboxylate esters Delta-lactones Total synthesis Bicyclic compounds Merck & Co. brands