Clinical pharmacology
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological
studies have established that elevated plasma levels of total cholesterol (total-C), LDL-C, and
apolipoprotein B (Apo B) promote human atherosclerosis and are risk factors for developing
cardiovascular disease, while increased levels of high-density lipoprotein cholesterol (HDL-C) and its
transport complex, Apo A-I, are associated with decreased cardiovascular risk. High plasma triglycerides
(TG) and cholesterol-enriched TG-rich lipoproteins, including very-low-density lipoproteins (VLDL),
intermediate-density lipoproteins (IDL), and remnants, can also promote atherosclerosis. Elevated plasma
TG are frequently found in a triad with low HDL-C and small LDL particles, as well as in association with
non-lipid metabolic risk factors for CHD. As such, total plasma TG has not consistently been shown to be
an independent risk factor for CHD. Furthermore, the independent effect of raising HDL-C or lowering TG
on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
In the Scandinavian Simvastatin Survival Study (4S), the effect of improving lipoprotein levels with
ZOCOR on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol (total-C)
212-309 mg/dL (5.5-8.0 mmol/L). The patients were followed for a median of 5.4 years. In this multicenter,
randomized, double-blind, placebo-controlled study, ZOCOR significantly reduced the risk of mortality by
30% (11.5% vs 8.2%, placebo vs ZOCOR); of CHD mortality by 42% (8.5% vs 5.0%); and of having ahospital-verified non-fatal myocardial infarction by 37% (19.6% vs 12.9%). Furthermore, ZOCOR
significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery
bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (17.2% vs 11.4%).
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 β-hydroxyacid, 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) in plasma following administration of simvastatin.
Following an oral dose of 14C-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 14C-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. Simvastatin undergoes extensive first-pass extraction in the liver, its
primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of
extensive hepatic extraction of simvastatin (estimated to be > 60% in man), the availability of drug to the
general circulation is low. In a single-dose study in nine healthy subjects, it was estimated that less than
5% of an oral dose of simvastatin reaches the general circulation as active inhibitors. Following
administration of simvastatin tablets, the coefficient of variation, based on between-subject variability, was
approximately 48% for the area under the concentration-time curve (AUC) for total inhibitory activity in the
general circulation.
Zocor (simvastatin)
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Clinical pharmacology
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