Lovastatin

Lovastatin, which is an inactive lactone, is hydrolysed after oral administration to the corresponding β-hydroxyacid. This is the major metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyses an early and rate-limiting step in the biosynthesis of cholesterol. In clinical trials lovastatin reduced the plasma concentration of total cholesterol and of LDL- and VLDL-cholesterol (low-density and very low-density lipoproteins) and also increased HDL-cholesterol (high-density lipoproteins) and reduced plasma triglycerides.

The active form of lovastatin is a specific inhibitor of HMG-CoA reductase, the enzyme that catalyses the conversion of HMG-CoA to mevalonate. As the conversion of HMG-CoA to mevalonate is an early step in the biosynthesis of cholesterol, treatment with lovastatin is thought not to cause accumulation of any toxic sterols. Moreover, HMG-CoA is rapidly converted to acetyl-CoA, which is involved in many biosynthetic processes in the body.

In animal studies lovastatin, after oral administration, has displayed high selectivity for the liver, where lovastatin can be measured in far higher concentrations than in other tissues. Lovastatin undergoes extensive first-pass metabolism in the liver, the substance’s primary site of action, with subsequent excretion in the bile. After oral administration of lovastatin to trial subjects 10% of the dose was excreted in the urine and 83% in the faeces. Both lovastatin and its beta-hydroxyacid are bound to human plasma proteins (>95%). Animal studies have shown that lovastatin crosses the blood/brain barrier and the placental barrier. Peak plasma concentrations of lovastatin and its active metabolites are reached in the course of 2-4 hours after administration. Linear plasma concentrations are seen up to a dosage of 120 mg lovastatin. With daily administration, steady state in plasma concentrations is reached after 2-3 days. When administered when fasting, concentrations of lovastatin and active metabolites corresponded to ⅔ of the plasma concentration obtained when administered immediately after a normal meal.

The risk of myopathy is increased in cases of high concentrations of HMG-CoA reductase inhibitor activity in plasma. Potent inhibitors of CYP3A4 can increase the plasma concentration of HMG-CoA reductase inhibitor activity and increase the risk of myopathy.

The repeated administration of lovastatin in high doses led to toxic effects in various animal species, which were attributable to an excessive pharmacological action. The main target organs were the liver and the CNS. In studies on dogs cataracts occurred in isolated cases after the administration of lovastatin in the high dose range; however, on the basis of AUC levels there seems to be a sufficiently high safety margin in relation to the human therapeutic dose.

No evidence of a genotoxic potential was found in a battery of (in-vitro and in-vivo) genetic toxicology studies.

An increased incidence of tumours (e.g. Hepatocellular carcinomas and adenomas, Pulmonary adenomas, and Papillomas in squamous epithelium of the gastric mucosa) was observed after the administration of lovastatin in long-term studies on mice and rat carried out to detect a tumorigenic potential.

The significance of these findings for long-term therapy in humans is still unclear.

In reproduction toxicology studies skeletal malformations occurred in the foetuses after the administration of high dosages (800 mg/kg/day) to rats and mice. In rabbits no malformations were observed in the offspring with dosages of up to 15 mg/kg/day (MTD).

Fertility was impaired in dogs with dosages from 20 mg/kg/day, but a fertility study in rats proved negative.