ABSTRACT
Lovastatin and simvastatin are potent competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Key inhibit the synthesis of cholesterol in cultured HepG23 cells, rat hepatocytes and in rats. The primary target organ of cholesterol synthesis inhibition by lovastatin and simvastatin is the liver. Lovastating and simvastatin lower levels of plasma cholesterol in rats, dogs and rabbits by inhibition the endogenous cholesterol synthesis and induction of LDL receptor in the liver.
Subject(s)
Anticholesteremic Agents , Cholesterol/blood , Lovastatin/analogs & derivatives , Lovastatin/pharmacology , Animals , Cells, Cultured , Cholesterol/biosynthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Liver/drug effects , Liver/metabolism , Receptors, LDL/biosynthesis , Receptors, LDL/drug effects , SimvastatinABSTRACT
The in vitro bile acid binding properties of 2 water-soluble, linear, cationic resins, poly-[(dimethylimino)trimethylene chloride] or 3,3-ione C1, and poly-diallyldimethylammonium chloride) or CAT-FLOC were determined. Both polymers were substantially more active than cholestyramine. All were compared for hypocholesterolemic effect in normo-cholesterolemic dogs. CAT-FLOC and 3,3-ionene C1, administered at 1.8 and 1.2 g/day, respectively, exhibited cholesterol-lowering action equivalent to cholesteryramine given at 12 g/day. The results of this study suggest that effective reduction of plasma cholesterol may be achieved with significantly lower doses of bile acid sequestrants.
Subject(s)
Anticholesteremic Agents/therapeutic use , Cation Exchange Resins/therapeutic use , Cholesterol/blood , Ion Exchange Resins/therapeutic use , Polyethylenes , Polymers/therapeutic use , Quaternary Ammonium Compounds/therapeutic use , Taurocholic Acid/metabolism , Animals , Binding Sites , Cholestyramine Resin/therapeutic use , Dogs , Drug Evaluation, Preclinical , In Vitro Techniques , Male , SolubilityABSTRACT
Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolini and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was shown to be 1,2,6,7,8,8a-hexahydro-beta, delta-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-hepatanoic acid delta-lactone. Mevinolin in the hydroxy-acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 microgram/kg). Furthermore, it was shown that mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 weeks with mevinolin at 8 mg/kg per day resulted in a 29.3 +/- 2.5% lowering of plasma cholesterol.
