HYPOLIPIDEMIC EFFECTS IN DOGS OF ML-236B, A COMPETITIVE INHIBITOR OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME A REDUCTASE

ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, significantly reduced both serum cholesterol and phospholipid levels in dogs, when used at a dosage higher than 10 mg/kg per day. Triglyceride levels were not consistently changed, but β- and pre-β-lipoproteins were preferentially reduced. Serum cholesterol levels were reduced by 44-45% at the higher dosage of 100-400 mg/kg per day (for 5 weeks) but ML-236B caused no significant changes in the cholesterol content of the liver and aorta and in the activities of serum GOT, GPT, CPK and lecithin : cholesterol acyltransferase. Fecal excretion of neutral sterols was unaffected but that of bile acids was markedly elevated by the drug. Under these conditions, hepatic cholesterol 7α-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis, showed no detectable changes. © 1979.