Hypolipidemic effect of NK-104, a potent HMG-CoA reductase inhibitor, in guinea pigs

• Published in: Atherosclerosis 1999-10, Vol.146 (2), p.259-270
• Main Authors: Suzuki, Hideo, Aoki, Taro, Tamaki, Taro, Sato, Fumiyasu, Kitahara, Masaki, Saito, Yasushi
• Format: Article
• Language: English
• Subjects: Animals; Apolipoproteins B - metabolism; Biological and medical sciences; Cholesterol - blood; Chromatography, High Pressure Liquid; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Fractional catabolic rate; General and cellular metabolism. Vitamins; Guinea pig; Guinea Pigs; HMG-CoA reductase inhibitor; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hyperlipidemias - drug therapy; Hyperlipidemias - metabolism; Hypolipidemic Agents - pharmacology; Lipoproteins, VLDL - antagonists & inhibitors; Lipoproteins, VLDL - metabolism; Liver - metabolism; Liver perfusion; Low density lipoprotein receptor; Male; Medical sciences; NK-104; Pharmacology. Drug treatments; Quinolines - pharmacology; Receptors, LDL - agonists; Receptors, LDL - biosynthesis; Simvastatin - pharmacology; Sterols - antagonists & inhibitors; Sterols - biosynthesis; Triglycerides - blood; Very low density lipoprotein secretion
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/S0021-9150(99)00146-X

The hypolipidemic effect of NK-104 and its mechanisms of action (effects on hepatic sterol synthesis, low density lipoprotein (LDL)-receptor expression and very low density lipoprotein (VLDL) secretion) were studied in guinea pigs using simvastatin as a reference substance. There was a dose-dependent and significant reduction of both plasma total cholesterol (17.4, 24.5 and 45.3% at 0.3, 1 and 3 mg/kg, respectively) and triglycerides (21.1 and 32.2% at 1 and 3 mg/kg, respectively) after 14-day administration of NK-104. Simvastatin at 30 mg/kg lowered plasma total cholesterol (25.0%) but not triglyceride levels. NK-104 (3 mg/kg) and simvastatin (30 mg/kg) inhibited hepatic sterol synthesis by approximately 80%, 3 h after dosing, and enhanced LDL receptor binding-capacity of liver membranes 1.5-fold after 14-day dosing. The former group accelerated LDL clearance somewhat more markedly than the latter, and increased fractional catabolic rate 1.8-fold (vs. 1.4-fold). Furthermore, only the NK-104 (3 mg/kg) suppressed VLDL secretion into the liver perfusate (triglyceride, 19.9%; apoB, 24.2%) with extensive reduction of hepatic sterol synthesis caused by prolonged action. These results indicate that NK-104 and simvastatin at 10 times the dosage of the former, similarly enhances hepatic LDL receptor; however, only NK-104 with prolonged action suppresses VLDL secretion to show higher cholesterol-lowering potency and triglyceride-reducing effect.