Hypolipidemic effect of NK-104, a potent HMG-CoA reductase inhibitor, in guinea pigs.
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.
Suzuki
H
H
Tokyo Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., Higashimurayama, Japan.
Aoki
T
T
Tamaki
T
T
Sato
F
F
Kitahara
M
M
Saito
Y
Y
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D006168:Guinea Pigs; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D011804:Quinolines / Q000494:pharmacology*; D011973:Receptors, LDL / Q000819:agonists / Q000096:biosynthesis; D019821:Simvastatin / Q000494:pharmacology; D013261:Sterols / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014280:Triglycerides / Q000097:blood
D001055:Apolipoproteins B; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008079:Lipoproteins, VLDL; D011804:Quinolines; D011973:Receptors, LDL; D013261:Sterols; D014280:Triglycerides; D002784:Cholesterol; D019821:Simvastatin; C108475:pitavastatin