Lovastatin oxidation

For the diene containing API lovastatin, oxidation of the diene to the corresponding epoxide occurs in the presence of air (149). 

The pharmacokinetic implications of these findings are not straightforward. One important factor that must also be considered is hepatic extraction, which is higher for lovastatin than for its hydroxy acid metabolite [188], Some lactones are useful prodrugs of HMG-CoA reductase inhibitors due to this organ selectivity coupled with the efficiency of enzymatic hydrolysis. However, other factors may also influence the therapeutic response, in particular the extent and rate of metabolic reactions that compete with or follow hydrolysis, e.g., cytochrome P450 catalyzed oxidations, /3-oxidation, and tau-... 

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. 

These compounds are structural analogs of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A, Figure 35-3). Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, and rosuvastatin belong to this class. They are most effective in reducing LDL. Other effects include decreased oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions. It has become standard practice to initiate reductase inhibitor therapy immediately after acute coronary syndromes, regardless of lipid levels. 

The effects of co-administration of oral diltiazem, a potent inhibitor of CYP3A, on the pharmacokinetics of lovastatin have been evaluated in a randomized study in 10 healthy volunteers (10). Lovastatin is oxidized by CYP3A to active metabolites. Diltiazem significantly increased the oral AUC and maximum serum concentration of lovastatin, but did not alter its half-life. The magnitude of the increase of plasma concentration of lovastatin suggested that caution is necessary when coadministering diltiazem and lovastatin. 

Under oxidative stress conditions, primary and secondary hydroxyls can be oxidized to the corresponding aldehyde and ketone derivatives. Oxidation of a secondary hydroxyl to a ketone (4 -oxolactone) is observed for the API lovastatin (Fig. 82) (123). 

Figure 82 Degradation of Lovastatin via oxidation of a secondary hydroxyl to a ketone.

It is clear from Equation (19.4) that saturated fat, not cholesterol, is the single most important factor that raises serum cholesterol. Some cases of hyperlipoproteinemia type IV (high VLDL) respond to low-carbohydrate diets, because the excess of VLDL comes from intestinal cells, where it is produced from dietary carbohydrate. Resins, such as cholestyramine and cholestipol, bind and cause the excretion of bile salts, forcing the organism to use more cholesterol. Lovastatin decreases endogenous cholesterol biosynthesis (see later), and niacin (nicotinic acid) apparently decreases the production of VLDL and, consequently, LDL. It also results in an HDL increase. Antioxidants that inhibit the conversion of LDL to oxidized LDL have also been used with some success. These are high doses of vitamin E and the drug probucol. 

Pahan K, Sheikh GF, Namboodiri AMS, Singh I (1997) Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microgha and macrophages. J Clin Invest 100 2671-2679. 

The clinical severity of statin-induced muscle toxicity is clearly influenced by variability in enzymes modulating statin disposition (absorption, distribution, metabolism, and elimination, ADME) (Fig. 1) [40], While many statins undergo phase I oxidation (atorvastatin, fluvastatin, lovastatin, simvastatin), the impact of phase I oxidation on others (pitavastatin, pravastatin, rosuvastatin) is very limited [41],... 

Wang, R.W., Kari, P.H., Lu, A.Y.H., Thomas, P.E., Guengerich, F.P. and Vyas, K.P. (1991) Biotransformation of lovastatin. IV. Identification of cytochrome P450 3A proteins as the major enzymes responsible for oxidative metabolism of lovastatin in rat and human liver microsomes. Archives... 

There are only a few reports in the literature on the use of isothermal microcalorimetry for the stability testing of pharmaceuticals (although in other fields, such as explosives, there are many more references testifying to a good degree of success). These include the degradation of P-lactam antibiotics (7), the oxidation of lovastatin (8), the hydrolysis of meclofenoxate hydrochloride (9), and the oxidation of d,l-a-tocopherol (10). 

The thermal properties of lovastatin, in particular those derived from DSC experiments, have been used to assess the oxidative stability of the compound (18,19). 

Oxidation of lovastatin in aerated ethylene dichloride solution at 35°, containing a free radical initiator, has been monitored kinetically using HPLC (34). The degradates formed in this complex solution system, different from those in the solid state, are primarily oligomers, with peroxide groups within the backbone chain and hydroperoxide end groups. Also, some monomeric epoxides are formed. 

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