RESUMEN
The preventive effects of simvastatin (MK-733) and pravastatin (CS-514), 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, on hypercholesterolemia induced by 0.25% cholesterol feeding were compared in rabbits. MK-733 (6, 2 and 0.7 mg/kg) was found to prevent the increase in serum total cholesterol levels dose-dependently. High dose CS-514 (18 mg/kg) also limited the increase in the cholesterol levels, but medium (6 mg/kg) and low doses (2 mg/kg) of CS-514 were ineffective in preventing it. MK-733 inhibited the increase in VLDL and LDL cholesterol levels dose-dependently. MK-733 suppressed the increase in serum phospholipid levels. MK-733 inhibited the accumulation of cholesterol in the liver. The high dose of CS-514 also limited it. High dose MK-733 (6 mg/kg) reduced the cholesterol concentration in gallbladder bile. Neither MK-733 nor CS-514 affected bile acid excretion in the gallbladder bile. High dose MK-733 decreased the lithogenic index. MK-733 increased the number of LDL receptors, and high dose CS-514 also increased it. The suppressive effect of CS-514 on serum cholesterol levels at 18 mg/kg was found to be less than that of MK-733 at 0.7 mg/kg.
Asunto(s)
Colesterol en la Dieta/administración & dosificación , Ácidos Heptanoicos/farmacología , Hipercolesterolemia/metabolismo , Lovastatina/análogos & derivados , Naftalenos/farmacología , Animales , Bilis/metabolismo , Colesterol/sangre , Hipercolesterolemia/inducido químicamente , Lipoproteínas/sangre , Lipoproteínas LDL/metabolismo , Lovastatina/farmacología , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Pravastatina , Conejos , Receptores de LDL/análisis , Receptores de LDL/efectos de los fármacos , Simvastatina , Estadística como Asunto , Esterol O-Aciltransferasa/análisis , Esterol O-Aciltransferasa/antagonistas & inhibidoresRESUMEN
The effects of Simvastatin (MK-733), an inhibitor of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, on fecal and biliary excretion of sterols and bile acids were examined using rabbits. Multiple doses of MK-733 (10 mg/kg/day) for 7 days were found to increase fecal concentrations of neutral sterols in cholesterol-fed rabbits, but not to affect those of bile acids. Multiple doses of cholestyramine (750 mg/kg/day), a bile acid sequestrant, for 7 days increased fecal concentrations of neutral sterols and bile acids in normally fed and cholesterol-fed groups. MK-733 did not affect biliary neutral sterols and total bile acids in normally fed and cholesterol-fed groups. Cholestyramine decreased biliary concentrations of neutral sterols in both diet groups. Cholestyramine altered fecal and biliary composition of bile acids, but MK-733 did not. It was considered that MK-733 inhibited the absorption of cholesterol, resulting in an increase of the fecal concentration of neutral sterols in cholesterol-fed rabbits. The mechanism of action of MK-733 in the inhibition of cholesterol absorption is considered to be clearly different from that of cholestyramine. These results confirmed the conclusion in the previous experiment.