Statins lovastatin

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. 

The statins, lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) resembles that of the physiological substrate of the enzyme (A). L and S are lactones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metabolites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective hepatic uptake of the mycotoxin, amanitin (A), Atorvastatin has the longest duration of action. 

Loops ethacrynic acid, furosemide, torsemide Bipyridines inamrinone, amrinone, milrmone, P agonists dobutamine, dopamine Statins lovastatin atorvastatin, etc Fibrates gemfibrozil... 

Fig. 12-12 The statin Lovastatin and for comparison with its structure, FiMG-CoA.

Cyclosporine increases the systemic exposure of all statins (lovastatin, simvastatin, pravastatin, cerivastatin, and rosuvastatin), due to drug-drug interaction (via either CYPs or transporters like P-gp and OATP) in the liver. Rosuvastatin has been shown to be a substrate for the human liver transporter OATP2 and BCRP, but not P-gp. It s metabolic clearance is low and mainly mediated by CYP2C9. CsA treatment in transplant recipients increased AUCq 2h and Cmax of rosuvastatin (10 mg) by 7.1 and 10.6-fold, respectively, compared with control values, due to CsA inhibition of OATP2-mediated rosuvastatin hepatic uptake (Simonson et al., 2004). 

Figure 6 5 Natural statins lovastatin, simvastatin, compactin, and pravastatin.

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... 

Some patients, in particular those with genetic forms of hypercholesterolemia (Table 9-2), will require three or more drugs to manage their disorder. Regimens using a statin, resin, and niacin were found to reduce LDL cholesterol up to 75%.42 These early studies were conducted with lovastatin, so larger reductions would be expected with the more potent statins available today. 

Reports about the influence of HMG-CoA-reductase inhibitors are conflicting (F7, H42, J8, K22, K29, L15, M3, S33, T5). In general, the effect is minimal or nonexistent some statins, such as simvastatin and lovastatin, are even reported to have an increasing influence (H42, J8, S33, Ul). Fibrates and derivatives are reported to exert a lowering effect (B13, F4, M3). 

Crestor Astra-Zeneca) and lovastatin + niacin (Advicor Kos Pharmaceutical) — that can also cause rhabdomyolysis remain on the market. Although scientists agree that the other statins "seem to have essentially identical safety profiles and benefif-risk rafios," FDA said the ADRs associated with Baycol "have been reported significantly more frequently than for other approved statins." ... 

Simvastatin is a semi-synthetic statin that is produced from the natural statin lovasta-tin7 Both are potent antihypercholesterolemic agents with simvastatin differing from lovastatin by just one additional methyl substituent residing on the 2-(5)-methylbutyrate side chain (Figure 1.6). 

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

The most important class of cholesterol-lowering agents is the statins. These include lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol), and atorvastatin (Lipitor), among others. These molecules work, in modest part, by inhibiting biosynthesis of cholesterol and, in larger part, by increasing the rate at which cholesterol is eliminated by the body. Let s have a look at this in more detail. 

Subsequently, a second, closely related molecule—lovastatin—was discovered by scientists at Merck in the United States in another fungal fermentation broth and by Sankyo in Japan. Lovastatin, marketed as Mevacor in the United States, proved both safe and efficacious for the intended nse and was the first statin to be approved for human use. Several others, some mentioned above, followed. The history of discovery and development of HMGR inhibitors has been pnUed together by Jonathan Tobert, who led the lovastatin and simvastatin clinical development effort at Merck. ... 

Simvastatin, a conjugated alkene, can polymerise as a result of peroxyl radical addition. The peroxide-linked oligomers can be subsequently cleaved to produce epoxides, which in turn degrade to form ketones and alcohols [69]. Inclusion of vitamin E (a-tocopherol) into formulations was found to inhibit chain-oxidation of simvastatin, lovastatin and other structurally related statins. 

Endocrine effects Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Small declines in total testosterone with no commensurate elevation in LH have been noted with the use of fluvastatin. Pravastatin showed inconsistent results with regard to possible effects on basal steroid hormone levels atorvastatin, lovastatin, rosuvastatin, and simvastatin did not reduce basal plasma cortisol concentration or basal plasma testosterone concentration or impair adrenal reserve. Appropriately evaluate patients who display clinical evidence of endocrine dysfunction. Exercise caution when administering HMG-CoA reductase inhibitors with drugs that affect steroid levels or activity, such as ketoconazole, spironolactone, and cimetidine. 

The statins may lower the risk of CHD by decreasing inflammation, an important component of atherogene-sis. Lovastatin decreased elevated plasma levels of C-reactive protein, a marker for cellular inflammation, and acute coronary events in patients with relatively low plasma cholesterol levels. Recent studies also suggest that use of statins may decrease the risk of stroke, dementia, and Alzheimer s disease and may improve bone... 

The introduction of the fungal metabolite lovastatin (26-9) has led to a sizeable class of clinically effective cholesterol lowering drugs. These agents, known familiarly as the statins, block an enzyme, HMG-CoA reductase, that is involved in the synthesis of mevalonate, an early precursor of cholesterol. Extensive work has... 

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