Zocor/Zocor HP Mechanism of Action

Antilipidemic Agent.
Pharmacology: Pharmacodynamics: SIMVASTATIN (ZOCOR) is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate. However, at therapeutic doses, the enzyme is not completely blocked, thereby allowing biologically necessary amounts of mevalonate to be available. Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway of cholesterol, therapy with SIMVASTATIN (ZOCOR) would not be expected to cause an accumulation of potentially toxic sterols. In addition, HMG-CoA is metabolized readily back to acetyl-CoA, that participates in many biosynthetic processes in the body.
Although cholesterol is the precursor of all steroid hormones, simvastatin has not been shown to have any clinical effect on steroidogenesis. Simvastatin caused no increase in biliary lithogenicity and, therefore, would not be expected to increase the incidence of gallstones.
Pharmacokinetics: Simvastatin is an inactive lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, L-654,969, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors). Both are measured in plasma following administration of simvastatin.
In a disposition study with ¹⁴C-labeled simvastatin, 100 mg (20 μCi) of drug was administered as capsules (5 X 20 mg), and blood, urine, and feces collected. Thirteen percent of the radioactivity was recovered in the urine and 60% in feces. The latter represents absorbed drug equivalents excreted in bile as well as unabsorbed drug. Less than 0.5% of the dose was recovered in urine as HMG-CoA reductase inhibitors. In plasma, the inhibitors account for 14 percent and 28 percent (active and total inhibitors) of the AUC of total radioactivity, indicating that the majority of chemical species present were inactive or weak inhibitors.
Both simvastatin and L-654,969 are bound to human plasma proteins (95%). The major metabolites of simvastatin present in human plasma are L-654,969 and four additional active metabolites. The availability of L-654,969 to the systemic circulation following an oral dose of simvastatin was estimated using an i.v. reference dose of L-654,969; the value was found to be less than 5% of the dose. By analogy to the dog model, simvastatin is well absorbed and undergoes extensive first-pass extraction in the liver, the primary site of action, with subsequent excretion of drug equivalents in the bile. Consequently, availability of active drug to the general circulation is low.
In dose-proportionality studies utilizing doses of simvastatin of 5, 10, 20, 60, 90 and 120 mg there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before a test meal.
The pharmacokinetics of single and multiple doses of simvastatin showed that no accumulation of drug occurred after multiple dosing. In all of the previously mentioned pharmacokinetic studies, the maximum plasma concentration of inhibitors occurred 1.3 to 2.4 hours post dose.
In a study of patients with severe renal insufficiency (creatinine clearance <30 mL/min), the plasma concentrations of total inhibitors after a single dose of a related HMG-CoA reductase inhibitor were approximately two-fold higher than those in healthy volunteers.
In a study of 12 healthy volunteers, simvastatin at the maximal 80-mg dose had no effect on the metabolism of the probe CYP3A4 substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1. (See Contraindications.)
In a pharmacokinetic study, concomitant administration of diltiazem caused a 2.7-fold increase in exposure of simvastatin acid, presumably due to inhibition of CYP3A4.
In a pharmacokinetic study, concomitant administration of amlodipine caused a 1.6-fold increase in exposure of simvastatin acid.
In a pharmacokinetic study, the coadministration of a single dose of niacin extended-release 2 g with simvastatin 20 mg resulted in a modest increase in the AUC of simvastatin and simvastatin acid and in the C_max of simvastatin acid plasma concentrations.
Specific pathways of fusidic acid metabolism in the liver are not known, however, an interaction between fusidic acid and HMG-CoA reductase inhibitors, which are metabolized by CYP3A4, can be suspected.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy (see Myopathy/Rhabdomyolysis under Precautions and Interactions).