Simvastatin, oxidation

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. 

Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998 101 271 I -2719. 

GZ. Simvastatin and losartan enhance nitric oxide and reduce oxidative stress in salt-induced hypertension. Am. J. Hypertens. 2005 18 1496-1502. 141. 

P. Di Napoli, A. A. Taccardi, A. Grilli, R. Spina, M. Fclaco, A. Barsotti, R. De Caterina, Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression an ex-vivo study in isolated working rat hearts, Cardiovasc Res 1,283-93 (2001). 

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],... 

The past decade has shown that hydrocarbon desaturation is not uncommon but, except in cases such as the biosynthesis of ergosterol, it generally accounts for a minor proportion of the metabolic products. The earliest reported example of P450-mediated hydrocarbon desaturation appears to be the conversion of lindane (1,2,3,4,5,6-hexachloro-cyclohexane) to 1,2,3,4,5,6-hexachlorocyclohex-ene, but the known hydrocarbon desaturation reactions now include the A -desaturation of androstenedione and deoxycorticosterone by adrenal mitochondria, the oxidation of dihydronaphthalene to naphthalene and 7,8-dihydrobenzo[a] pyrene to benzo[a]pyrene the conversion of warfarin to dehydrowarfarin ", the desaturation of lovostatin and simvastatin to the 6-exo-methylene... 

Sigmatropic rearrangement, 958 Silk, 1085 Siloac, Edward, 272 Silver oxide, 883, 958, 964 Simmons, Howard E., 564 Simmons-Smith reaction (reagent), 564 Simvastatin, 1038 Sinigrin, 989... 

Ceriello A, Tabga C, Tonutti L, et al. Evidence for an independent and cumulative effect of postprandial hypertriglyceridaemia and hyperglycaemia on endothelial dysfunction and oxidative stress generation. Effects of short and long-term simvastatin therapy. Circulation. 2002 106 1211-1218. 

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