Taro Tamaki

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.

Triglyceride-lowering effect of pitvastatin in a rat model of postprandial lipemia

Abstract The triglyceride-lowering effect of pitavastatin, a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was investigated in a rat model of postprandial lipemia. Plasma triglyceride levels started to increase 4 h after the fat load, reached the maximum at 6 h and then gradually decreased. A single dose of pitavastatin (1 mg/kg) significantly suppressed chylomicron-triglyceride secretion into the lymph by 40% and delayed the elevation of plasma triglyceride. Pitavastatin at 1 mg/kg decreased the 6-h plasma triglyceride levels by 53% and at 0.5 mg/kg decreased the 0–12 h area under the curve (AUC) of triglyceride levels by 56%. Atorvastatin also caused decreases, but to a lesser extent. Pitavastatin, and atorvastatin to a lesser extent, reduced the activity of the intestinal microsomal triglyceride transfer protein (MTP) at 6 h. These results suggested that a single dose of pitavastatin lowered postprandial triglyceride levels in rats by decreasing chylomicron-triglyceride secretion, probably through a reduction of intestinal MTP activity and triglyceride droplet formation in the endoplasmic reticulum.