Chemical formula: C₂₃H₃₆O₇ Molecular mass: 424.528 g/mol PubChem compound: 54687
Pravastatin is a competitive inhibitor of 3-hydroxy–3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme catalyzing the early rate limiting step in cholesterol biosynthesis, and produces its lipid lowering effect in two ways.
Firstly, with the reversible and specific competitive inhibition of HMG-CoA reductase, it effects modest reduction in the synthesis of intracellular cholesterol. This results in an increase in the number of LDL-receptors on cell surfaces and enhanced receptor-mediated catabolism and clearance of circulating LDL-cholesterol.
Secondly, pravastatin inhibits LDL production by inhibiting the hepatic synthesis of VLDL-cholesterol, the LDL-cholesterol precursor.
In both healthy subjects and patients with hypercholesterolaemia, pravastatin sodium lowers the following lipid values: total cholesterol, LDL-cholesterol, apolipoprotein B, VLDL-cholesterol and triglycerides; while HDL-cholesterol and apolipoprotein A are elevated.
Pravastatin is administered orally in the active form. It is rapidly absorbed; peak serum levels are achieved 1 to 1.5 hours after ingestion. On average, 34% of the orally administered dose is absorbed, with an absolute bioavailability of 17%.
The presence of food in the gastrointestinal tract leads to a reduction in the bioavailability, but the cholesterol–lowering effect of pravastatin is identical whether taken with or without food.
After absorption, 66% of pravastatin undergoes a first pass extraction through the liver, which is the primary site of its action and the primary site of cholesterol synthesis and clearance of LDL-cholesterol. In vitro studies demonstrated that pravastatin is transported into hepatocytes and with substantially less intake in other cells. In view of this substantial first pass through the liver, plasma concentrations of pravastatin have only a limited value in predicting the lipid-lowering effect.
The plasma concentrations are proportional to the doses administered.
About 50% of circulating pravastatin is bound to plasma proteins. The volume of distribution is about 0.5 l/kg. A small quantity of pravastatin passes into the human breast milk.
Pravastatin is not significantly metabolised by cytochrome P450 nor does it appear to be a substrate or an inhibitor of p-glycoprotein but rather a substrate of other transport proteins.
Following oral administration, 20% of the initial dose is eliminated in the urine and 70% in the faeces. Plasma elimination half-life of oral pravastatin is 1.5 to 2 hours.
After intravenous administration, 47% of the dose is eliminated by renal excretion and 53% by biliary excretion and biotransformation. The major degradation product of pravastatin is the 3-α-hydroxy-isomeric metabolite. This metabolite has one–tenth to one-fortieth the HMG-CoA reductase inhibitor activity of the parent compound.
The systemic clearance of pravastatin is 0.8 l/h/kg and the renal clearance is 0.38l/h/kg indicating tubular secretion.
Mean pravastatin Cmax and AUC values for paediatric subjects pooled across age and gender were similar to those values observed in adults after a 20 mg oral dose.
Systemic exposure to pravastatin and metabolites in patients with alcoholic cirrhosis is enhanced by about 50% comparatively to patients with normal liver function.
No significant modifications were observed in patients with mild renal impairment. However severe and moderate renal insufficiency may lead to a two-fold increase of the systemic exposure to pravastatin and metabolites.
Based on conventional studies of safety pharmacology, repeated dose toxicity and toxicity on reproduction, there are no other risks for the patient than those expected due to the pharmacological mechanism of action.
Repeated dose studies indicate that pravastatin may induce varying degrees of hepatotoxicity and myopathy; in general, substantive effects on these tissues were only evident at doses 50 or more times the maximum human mg/kg dose.
In vitro and in vivo genetic toxicology studies have shown no evidence of mutagenic potential.
In mice a 2-year carcinogenicity study with pravastatin demonstrates at doses of 250 and 500 mg/kg/day (≥310 times the maximum human mg/kg dose) statistically significant increases in the incidence of hepatocellular carcinomas in males and females, and lung adenomas in females only.
In rats a 2-year carcinogenicity study demonstrates at a dose of 100 mg/kg/day (125 times the maximum human mg/kg/dose) a statistically significant increase in the incidence of hepatocellular carcinomas in males only.
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