Pharmacological Properties of YM17E, an Acyl-CoA : Cholesterol Acyltransferase Inhibitor, and Diarrheal Effect in Beagle Dogs

この論文にアクセスする

この論文をさがす

著者

    • UTIDA Taisuke
    • Drug Metabolism Department, Yamanouchi Pharmaceutical Co., Ltd.
    • NAGANUMA Shin
    • Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Institute for Drug Discovery Research
    • KASKUTA Hirotoshi
    • Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Institute for Drug Discovery Research
    • TERADA Motoko
    • Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Institute for Drug Discovery Research
    • KIRIYAMA Takashi
    • Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Institute for Drug Discovery Research
    • MATSUDA Koyo
    • Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Institute for Drug Discovery Research
    • ITO Noriki
    • Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Institute for Drug Discovery Research
    • IIZUMI Yuichi
    • Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Institute for Drug Discovery Research
    • TAKWNAKA Toichi
    • Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi Institute for Drug Discovery Research

抄録

YM17E (1, 3-bis[[1-cycloheptyl-3-(<I>p</I>-dimethylaminophenyl)ureido]methyl]benzene dihydrochloride)was found to be a potent inhibitor of acyl-CoA: cholesterol acyltransferase (ACAT)in rabbit liver and intestine microsomes. Dixon plot analysis revealed that YM17E inhibited microsomal ACAT in a non-competitive manner. YM17E induced a marked decrease in serum cholesterol, especially in non-highdensity lipoprotein (HDL)fractions, in cholesterol-fed rats and rats fed normal chow. Measurement of bile secretion after oral administration of YM17E in cholesterol-fed rats showed that the drug markedly accelerated the secretion of bile acids and neutral sterols. Furthermore, absorption of [<SUP>3</SUP>H]cholesterol from the gut of cholesterol-fed rats was significantly inhibited by YM17E. From these results, the hypocholesterolemic activity of YM17E in these animals resulted from both a decrease in cholesterol absorption from the gut and the stimulation of excretion of cholesterol from the liver into bile. However, YM17E caused secretory diarrhea in beagle dogs at near lipid lowering doses. When YM17E was administered at the same total dosage but divided into 5 daily administrations, the incidence of diarrhea was significantly reduced while its cholesterol lowering effect became stronger. These results suggest that the inhibition of intestinal and/or liver ACAT increases the risk of diarrhea development which, however, can be avoided by controlled drug administration in beagle dogs.

収録刊行物

  • The Japanese journal of pharmacology

    The Japanese journal of pharmacology 73(1), 41-50, 1997-01-01

    The Japanese Pharmacological Society

参考文献:  27件中 1-27件 を表示

被引用文献:  5件中 1-5件 を表示

各種コード

  • NII論文ID(NAID)
    10008676832
  • NII書誌ID(NCID)
    AA00691188
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    00215198
  • NDL 記事登録ID
    4131794
  • NDL 雑誌分類
    ZS51(科学技術--薬学)
  • NDL 請求記号
    Z53-D199
  • データ提供元
    CJP書誌  CJP引用  NDL  J-STAGE 
ページトップへ