RG 12561 (Dalvastatin): A Novel Synthetic Inhibitor of HMG-CoA Reductase and Cholesterol-Lowering Agent

Abstract

RG 12561 (dalvastatin) is a prodrug which converts to its open hydroxyacid form in the body. The Na salt of RG 12561 (RG 12561-Na) is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. It competitively inhibits rat liver HMG-CoA reductase with an IC50 value of 3.4 nmol/l. In the same assay, the IC50 values for other potent HMG-CoA reductase inhibitors, lovastatin-Na and pravastatin, were 2.3 and 8.9 nmol/l, respectively. In Hep G2 liver cells, RG 12561-Na, lovastatin-Na and pravastatin inhibited cholesterol biosynthesis from radiolabeled octanoate with IC50 values of 4 and 5 nmol/l and 1.1 μmol/l, respectively. In a rat ex vivo assay, orally administered RG 12561 lovastatin and pravastatin inhibited cholesterol biosynthesis in liver slices with ED₅₀ values of 0.9, 0.5 and 12 mg/kg, respectively. In cholestyramine-fed hamsters, RG 12561 (0.1% in food for 18 days) reduced LDL cholesterol, whereas HDL was slightly increased. The reductions in the LDL/HDL ratio for RG 12561, RG 12561-Na, lovastatin and lovastatin-Na were 35, 76, 88 and 88%, respectively. At a higher dose, RG 12561 (0.4% in food) reduced serum cholesterol, LDL and LDL/HDL by 84, 97 and 91 %, respectively. In WHHL rabbits, RG 12561 and lovastatin (5 mg/kg, b.i.d., 12 days) reduced serum cholesterol by 17 and 16 %, respectively. These results demonstrate that RG 12561 is a potent cholesterol-lowering agent.

Effects of Single Administered Bofutsushosan-Composed Crude Drugs on Diabetic Serum Parameters in Streptozotocin-Induced Diabetic Mice

“…Inhibition of HMG-CoA reductase decreases cholesterol synthesis. The inhibition of HMG-CoA reductase is very effective in lowering serum cholesterol and LDL in most of animal species, including humans [27]. All of these results suggest that BOF has two mechanisms for lowering effects on serum cholesterol level.…”

4-Hydroxycinnamate Lowers Plasma and Hepatic Lipids without Changing Antioxidant Enzyme Activities

“…This may be due to differences in the lipoprotein metabolism between animal species [49]. The HMG-CoA reductase inhibitor dosages usually have to be very high to produce a hypocholesterolemic response in rats [50,51]. Meanwhile, hepatic ACAT is involved in the formation of cholesteryl esters, which is important for cholesterol absorption, hepatic very-low-density lipoprotein (VLDL) cholesterol sclerosis [13].…”

“…The two key enzymes involved in the regulation of cholesterol metabolism are 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase and acyl coenzyme A:cholesterol acyltransferase (ACAT). HMG-CoA reductase inhibitors are very effective in lowering serum cholesterol in most animal species as well as in humans [8][9][10][11], and the inhibitors are now widely used as hypocholesterolemic drugs [12]. ACAT is an intracellular enzyme that catalyzes the formation of cholesteryl ester from cholesterol and fatty acyl coenzyme A [13].…”

Cholesterol-Lowering Activity of Naringenin via Inhibition of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase and Acyl Coenzyme A:Cholesterol Acyltransferase in Rats

“…Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in the decrease of cholesterol synthesis in cells. HMG-CoA reductase inhibitors are very effective in lowering serum cholesterol in most animal species as well as in humans [2][3][4][5], and the inhibitors are now widely used as hypocholesterolemic drugs [6]. Acyl coenzyme A:cholesterol O-acyltransferase (ACAT) is a key enzyme catalyzing the intracellular esterification of cholesterol.…”