title: Cholesterol-lowering effect of NK-104, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, in guinea pig model of hyperlipidemia.
abstract: Although benefits of statins have been demonstrated even in normolipidemic patients at high risk, the main target of statin therapy is the hypercholesterolemic patient. The aim of this study was to examine the hypocholesterolemic effect of NK-104 ((+)-monocalcium bis((3R,5S,6S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]- 3,5-dihydroxy-6-heptenoate), CAS 147526-32-7), a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and its mechanism of action in hypercholesterolemic animals. In guinea pigs fed a diet containing 15% (w/w) fat rich in laurate for 6 weeks, the liver cholesterol content was markedly increased and plasma total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and LDL-apoB were elevated 4.8, 5.2 and 1.7 times, respectively, compared with normal diet fed animals. These changes were maintained by reduced LDL clearance in the presence of markedly cholesterol-enriched LDL in the plasma. In this model, the LDL-C reduction rates by 0.1, 0.3 and 1 mg/kg of NK-104 orally administered for 2 weeks (from week 4 to week 6), were 11, 27 and 32%, respectively, from controls, being similar in normal guinea pigs previously examined. Those for 3 and 10 mg/kg of atorvastatin (CAS 134523-00-5) were 25 and 39%, respectively. Thus about 10 times higher doses of atorvastatin were required than of NK-104 to cause a similar cholesterol-lowering effect. This reduction of plasma cholesterol was accompanied by an improvement of LDL clearance (24 and 47% increase in fractional catabolic rate by 1 mg/kg of NK-104 and 10 mg/kg of atorvastatin, respectively) and LDL composition. In conclusion, in guinea pig hypercholesterolemia caused by high-laurate diet, NK-104 and atorvastatin lowered plasma cholesterol levels with an improvement of LDL composition and with an increase in LDL clearance, presumably through reduction of the liver cholesterol content, although hepatic cholesterol synthesis might have been markedly suppressed in this model.
authors: Tokyo Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., Higashimurayama, Tokyo, Japan. t-aoki@kowa.co.jp
authors: T
authors: T
authors: Aoki
authors: H
authors: H
authors: Yamazaki
authors: H
authors: H
authors: Suzuki
authors: T
authors: T
authors: Tamaki
authors: F
authors: F
authors: Sato
authors: M
authors: M
authors: Kitahara
authors: Y
authors: Y
authors: Saito
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D000069059:Atorvastatin; D004032:Diet; D006168:Guinea Pigs; D006538:Heptanoic Acids / Q000627:therapeutic use; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy*; D007850:Lauric Acids / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011758:Pyrroles / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D007850:Lauric Acids; D008055:Lipids; D008077:Lipoproteins, LDL; D011758:Pyrroles; D011804:Quinolines; D014280:Triglycerides; C030358:lauric acid; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; C108475:pitavastatin