In 1998, the US Food and Drug Administration (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.
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.
However, in 1980, trials with compactin were suspended for undisclosed reasons (rumoured to be related to serious animal toxicity). Because of the close structural similarity between compactin and lovastatin, clinical studies with lovastatin were also suspended, and additional animal safety studies initiated.
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 resumed.
Large-scale trials confirmed the effectiveness of lovastatin. Observed tolerability continued to be excellent, and lovastatin was approved by the US FDA in 1987.
Lovastatin at its maximal recommended dose of 80 mg daily produced a mean reduction in LDL cholesterol of 40%, a far greater reduction than could be obtained with any of the treatments available at the time. Equally important, the drug produced very few adverse effects, was easy for patients to take, and so was rapidly accepted by prescribers and patients. The only important adverse effect is myopathy/rhabdomyolysis. This is rare and occurs with all HMG-CoA reductase inhibitors.
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 having a formal sterol ring.
Lovastatin is 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 discovery of mevastatin, a highly functionalized fungal metabolite, isolated from cultures of Penicillium citrium. Mevastatin was demonstrated to be an unusually potent inhibitor of the target enzyme and of cholesterol biosynthesis. Subsequent to the first reports describing mevastatin, efforts were initiated to search for other naturally occurring inhibitors of HMG CoA reductase. This led to the discovery of a novel fungal metabolite – Lovastatin. The structure of Lovastatin was determined to be different from that of mevastatin by the presence of a 6 alphamethyl group in the hexahydronaphthalene ring.
Key points from the study of the Biosynthesis of Lovastatin :-
Lovastatin is comprised of 2 polyketide chains derived from acetate that are 8- and 4- carbons long coupled in head to tail fashion.
6 alphamethyl group and the methyl group on the 4-carbon side chain are derived from the methyl group of methionine, and
6 alphamethyl group is added before closure of the rings.
This implies that lovastatin is a unique compound synthesized by A. terreus and that mevastatin is not an intermediate in its fornmation.
In vitro formation of a triketide lactone using a genetically-modified protein derived from 6-deoxyerythronolide B synthase has been demonstrated. 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.
It has been found that a dedicated acyltransferase, LovD, is encoded in the lovastatin biosynthetic pathway. LovD has a broad substrate specificity towards the acyl carrier, the acyl substrate and the decalin acyl acceptor. It efficiently catalyzes the acyl transfer from coenzyme A thoesters or N-acetylcysteamine (SNAC) thioesters to monacolin J.
The biosynthesis of Lovastatin is coordinated by two iterative type I polyketide syntheses and numerous accessory enzymes. Nonketide, the intermediate biosynthetic precursor of Lovastatin, is assembled by the upstream megasynthase LovB (also known as lovastatin nonaketide synthase), enoylreductase LovC, and CYP450 oxygenases. The five carbon unit side chain is synthesized by LovF (also known as lovastatin diketide synthase) through a single condensation diketide undergoes methylation and reductive tailoring by the individual LovF catalytic domains to yield an α-S-methylbutyryl thioester covalently attached to the phosphopantetheine arm on the acyl carrier protein (ACP) domain of LovF. Encoded in the gene cluster is a 46kDa protein, LovD, which was initially identified as an esterase homolog. LovD, which was initially identified as an esterase homolog. LovD was suggested to catalyze the last step of lovastatin biosynthesis that regioselectively transacylates the acyl group from LovF to the C8 hydroxyl group of the Nonaketide to yield Lovastatin.
Simple organic reactions were used to get to Lovastatin as shown in the scheme.
Lovastatin causes cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL (low density lipoprotein) particles. Apolipoprotein B concentration falls substantially during treatment with lovastatin. Lovastatin's ability to lower LDL is thought to be due to a reduction in VLDL, which is a precursor to LDL. Also, Lovastatin may increase the number of LDL receptors on the surface of cell membranes, and thus increase the breakdown of LDL.
Lovastatin can also produce slight to moderate increases in HDL, and slight to moderate decreases in triglycerides. Both of these effects are typically beneficial to a patient with a poor lipid profile.
Both lovastatin and its b-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers. Elderly patients, or those with renal insufficiency may have higher plasma concentrations of lovastatin after administration and may require a lower dose. The usual recommended starting dose is 20 mg once a day given with the evening meal, and the dose range is 10-80 mg a day in a single dose, or divided into two doses.
Lovastatin at doses higher than 20 mg per day should not be used in conjunction with gemfibrozil or other fibrates, niacin, or cyclosporin. This is because of the significantly increased risk of rhabdomyolysis.
Lovastatin tablets are tested for Dissolution and Assay as per the USP.
Limit for Dissolution – Not less than 80% (Q) of the labeled amount of Lovastatin is dissolved in 30 mins.
Limit for Assay – Each tablet contains not less than 90% and not more than 110% of the labeled amount of Lovastatin, tested by HPLC analysis.
Lovastatin raw material contains 5 impurities – A, B, C, D and E (as shown below).