Effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in Watanabe heritable hyperlipidemic rabbits and cholesterol-fed rabbits.
The aim of this study was to evaluate the effects of (+)-(E)-6S-(2-(4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (HR780), a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on hypercholesterolemia in Watanabe heritable hyperlipidemic (WHHL) rabbits and rabbits fed a diet with 1% cholesterol, in comparison with the effects of simvastatin. Each drug was administered orally to WHHL rabbits for 24 weeks and to 1% cholesterol-fed rabbits for 10 weeks. In WHHL rabbits, HR780 at doses of 1, 2.5 and 5 mg/kg/day reduced the plasma total cholesterol level by 15, 24 and 20%, respectively. In contrast, simvastatin at 5 mg/kg/day lowered the level by 23%. In 1% cholesterol-fed rabbits, HR780 (1 and 2.5 mg/kg/day) was found to inhibit the increases in the plasma total cholesterol and phospholipid levels and liver cholesterol contents in a dose-dependent manner. Simvastatin (5 mg/kg/day) also inhibited their increase. Neither HR780 nor simvastatin increased the contents of cholesterol and total bile acid in the gallbladder bile. In conclusion, long-term treatment with HR780 reduced the plasma cholesterol level in WHHL rabbits and 1% cholesterol-fed rabbits, and decreased the liver cholesterol contents in 1% cholesterol-fed rabbits.
Wajima
Teruaki
T
Pharmacology, Aventis Pharma Ltd., Kawagoe, Saitama, Japan. teruaki.wajima@aventis.com
Makita
Shigeki
S
Oshima
Kenichi
K
D000818:Animals; D030801:Animals, Genetically Modified; D001646:Bile / Q000737:chemistry; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage* / Q000009:adverse effects; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000235:genetics*; D007564:Japan; D008055:Lipids / Q000097:blood; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D019821:Simvastatin / Q000627:therapeutic use
D002791:Cholesterol, Dietary; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011725:Pyridines; C062437:HR 780; D002784:Cholesterol; D019821:Simvastatin