Lovastatin

Filamentous fungi generate a chemically diverse array of bioactive, low molecular weight compounds, termed secondary metabolites. Secondary metabolites are dispensable for 

Aspergillus-denved statins are an excellent example of fungal secondary metabolites that have made a great impact to human health as a drug. Statins are widely used for reducing plasma concentrations of total and LDL cholesterol in the treatment of hypercholesterolemia and reducing the risk of heart attacks. Statins are hydroxymethylglutaryl-coenzyme 

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The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

In the first clinical studies with lovastatin, pte-dmg semm cholesterol values of 150—300 mg/dL were shown to be decreased as much as 25% with a dosage of 15 mg twice daily for just over a week (149). Whereas the dmg shows few adverse side effects, gastrointestinal disturbances, including diarrhea and abdominal pain, ate the most common. 

Lovastatin is administered as an inactive lactone. After oral ingestion, it is hydrolyzed to the active mevinolinic acid, a competitive inhibitor of the reductase with a Ki of 0.6 nM. Mevinolinic acid is thought to behave as a transition-state analog (Chapter 16) of the tetrahedral intermediate formed in the HMG-CoA reductase reaction (see figure). 

Derivatives of lovastatin have been found to be even more potent in cholesterol-lowering trials. Synvinolin lowers serum cholesterol levels at much lower doses than lovastatin. 

The structures of (inactive) lovastatin, (active) mevinolinic acid, mevalonate, and synvinolin. 

FIGURE 7.2 Model of LFA-1 showing the binding domain of ICAM-1 (the endogenous ligand for this protein) and the binding site for lovastatin, an allosteric modulator for this protein. Redrawn from [7],... 

Lovastatin, simvastatin Ketoconazole, erythromycin, etc. CYP3A4 Rhabdomyolysis... 

There are currently marketed four naturally derived statins (lovastatin, pravastatin, simvastatin, and rosuvas-tatin) and two synthetic statins (atorvastatin and fluvas-tatin). The structure of these statins is shown in Fig. 2. 

A prodrag is a drug that is not by itself pharmacologically active but needs metabolic activation by an enzyme. Examples are the cytostatic cyclophosphamide, which is activated by hydroxylation catalyzed by CYP2B6, or HMGCoA reductase inhibitor, lovastatin, which contains... 

Lovastatin is taken once daily, preferably with the evening meal. Fluvastatin, pravastatin, and simvastatin are taken, witiiout regard to meals, once daily in die evening or at bedtime... 

In some cases enzymes can increase the rate of reaction by up to lO times. Carnell and Roberts (1997) have briefly discussed the scope of biotransformations that are used to make pharmaceuticals like penicillins, cephalosporines, erythromycin, lovastatin, cyclosporin, etc., and for food additives like citric acid, L-glutamate, and L-lysine. A very successful transformation by Zeneca has been that of benzene reduction, with Pseudomonase Putida, to dihydrocatechol and catechol the dihydro derivative is used to produce (+/-) pinitol. Fluorobenzene has been converted to fluorodihydrocatechol, an intermediate for pharmaceuticals. The highly stereo selective Bayer-Villeger reaction has been carried out with genetically engineered S-cerevisvae. Hydrolases have allowed enantioselective, and in some cases regioselective, hydrolysis of racemic esters. 

Diclofenac, fenofibrate, lovastatin, methyldopa, minocycline, nitrofurantoin, phenytoin, and propylthiouracil... 

Acetaminophen, bosentan, diclofenac, isoniazid, lovastatin, methyldopa, niacin, nefazodone, phenytoin, propylthiouracil, rifampin, trazodone, valproic acid, and venlafaxine... 

Over the last decade, several studies in tens of thousands of patients have revealed that lowering cholesterol, specifically lowering LDL cholesterol with statins, is effective for both primary and secondary prevention of IHD-related events. Statins shown to decrease morbidity and mortality associated with IHD include lovastatin, simvastatin, pravastatin, and atorvas-tatin.22,23 A recent meta-analysis showed that the risk of major adverse cardiac events is reduced by 21% with the use of statins in patients at high risk for IHD-related events.23... 

Lovastati n 1 0, 20, 40 mg tablets 1 0 to 80 mg/day as a single dose (with evening meal) or divided twice daily with food Approximate equivalent doses of HMG-CoA reductase inhibitors are atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40 mg, pravastatin 40 mg, simvastatin 20 mg, and rosuvastatin 5 mg. 

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