Lovastin Mechanism of Action

Cholesterol-lowering agent.
Pharmacology: Lovastatin is converted in vivo by esterases to the corresponding open hydroxyacid which is a potent inhibitor of endogeneous cholesterol synthesis.
Lovastatin is a cholesterol-lowering agent isolated from a strain of A. terreus. After oral ingestion, lovastatin which is an inactive lactone, is hydrolysed to the corresponding β-hydroxyacid form. This principal metabolite is a specific inhibitor of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase. This enzyme catalyses the conversion of HMG-CoA to mevalonate which is an early and rate-limiting step in the biosynthesis of cholesterol.
Lovastatin reduces cholesterol production by the liver and induces some changes in cholesterol transport and disposition in the blood and tissues. The mechanism of this effects is believed to involve both reduction of the synthesis of low-density lipoprotein (LDL) and in increase in LDL catabolism as a result of induction of the hepatic LDL receptors. The mechanism of the LDL-lowering effects of lovastatin may also involve reduction of the very low-density lipoprotein cholesterol concentration.
Pharmacokinetics: Following an oral dose of ¹⁴C-labeled lovastatin in man, 10% of the dose was excreted in the urine and 83% in the feces. The latter represents the absorbed as well as any unabsorbed drug that is excreted in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of drug to the general circulation is low and variable.
Both lovastatin and β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins. The major active metabolites present in human are the β-hydroxyacid of lovastatin, it 6'-hydroxy derivative and 2 unidentified metabolites. Peak plasma concentrations of both active and total inhibitors were attained within 2-4 hrs of dose administration.
With a once-a-day dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state between the 2nd and 3rd days of therapy and were about 1.5 times those following a single dose.