Mevastatin

Mevastatin is a cholesterol-lowering agent isolated from Penicillium citinium. It reduces cholesterol synthesis to 50% of control at 0.01 pg/mL (26 nM). ^[1] It is structurally similar to the HMG, a substituent of the endogenous substrate of HMG-CoA reductase. Mevastatin is a prodrug that is activated in vivo via hydrolysis of the lactone ring. The hydrolyzed lactone ring mimics the tetrahedral intermediate produced by the reductase allowing the agent to bind with 10,000 times greater affinity than its natural substrate. The bicyclic portion of mevastatin binds to the coenzyme A portion of the active site. Mevastatin increases levels of eNOS mRNA and protein, reduces infarct size, and improves neurological deficits in a dose- and time-dependent manner.^[2]

At doses of 5 and 20 mg/kg, mevastatin produces reduction of serum cholesterol levels at 3 hours after oral administration. It lowers the levels of serum cholesterol by approximately 30 % at a dose of 20 mg/kg. ^[1] Mevastatin lowers hepatic production of cholesterol by competitively inhibiting HMG-CoA reductase. Cholesterol levels are reduced only after 28 days of treatment and does not correlate with infarct reduction. Baseline absolute cerebral blood flow is 30% higher after 14-day high-dose treatment. ^[2]