Zocor

[simvastatin]

ZOCOR has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very-low-density lipoprotein (VLDL) and is catabolized predominantly by the high-affinity LDL receptor. The mechanism of the LDL-lowering effect of ZOCOR may involve both reduction of VLDL cholesterol concentration, and induction of the LDL receptor, leading to reduced production and/ or increased catabolism of LDL-C. Apo B also falls substantially during treatment with ZOCOR. As each LDL particle contains one molecule of Apo B, and since in patients with predominant elevations in LDL-C (without accompanying elevation in VLDL) little Apo B is found in other lipoproteins, this strongly suggests that ZOCOR does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, ZOCOR reduces VLDL and TG and increases HDL-C. The effects of ZOCOR on Lp( a), fibrinogen, and certain other independent biochemical risk markers for CHD are unknown. ZOCOR is a specific inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.

Pharmacokinetics

Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding -hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the -hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin.

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Following an oral dose of 14 C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. Plasma concentrations of total radioactivity (simvastatin plus 14 C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Absorption of simvastatin, estimated relative to an intravenous reference dose, in each of two animal species tested, averaged about 85% of an oral dose. In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues.

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