Experimental model of escape phenomenon in hamsters and the effectiveness of YM-53601 in the model.
1. The aim of this study was to establish an experimental model of the escape phenomenon, in which plasma cholesterol, initially reduced by a 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor such as pravastatin, increases again on long-term administration. We also evaluated the efficacy of YM-53601 ((E)-2-[2-fluoro-2- (quinuclidin-3-ylidene) ethoxy]-9H-carbazole monohydrochloride), a squalene synthase inhibitor, in this model. 2. Pravastatin inhibited cholesterol biosynthesis in hamster primary hepatocytes (IC(50), 14 nM). After pre-treatment with pravastatin, in contrast, almost no effect on cholesterol biosynthesis was seen. 3. In hamsters fed a high fat diet, 3 mg kg(-1) pravastatin for 9 days decreased plasma non-HDL cholesterol (total cholesterol - high density lipoprotein cholesterol) (P<0.01), but this effect was lost between 17 and 27 days of treatment, accompanied by an increase in HMG-CoA reductase activity. No such increase in plasma non-HDL cholesterol was seen with YM-53601 at 30 mg kg(-1) after 9 (P<0.001), 17 (P<0.01) or 27 (P<0.001) days of treatment. Replacement of pravastatin with YM-53601 caused a decrease in plasma non-HDL cholesterol by 53% (P<0.001) and in HMG-CoA reductase activity. 4. This animal model thus satisfactorily replicates the escape phenomenon observed in humans and may therefore be useful in evaluation of lipid-lowering agents, specifically comparison of HMG-CoA reductase inhibitors. Further, YM-53601 may be useful in the treatment of hypercholesterolemia without induction of the escape phenomenon.
Ugawa
Tohru
T
Cardiovascular Diseases Research, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. ugawa@yamanouchi.co.jp
Kakuta
Hirotoshi
H
Moritani
Hiroshi
H
Shikama
Hisataka
H
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood*; D006224:Cricetinae; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008647:Mesocricetus; D017035:Pravastatin / Q000494:pharmacology / Q000627:therapeutic use; D011812:Quinuclidines / Q000494:pharmacology* / Q000627:therapeutic use
D000924:Anticholesteremic Agents; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011812:Quinuclidines; C414830:YM 53601; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D017035:Pravastatin