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

Access this Article

Author(s)

    • 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

Abstract

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.

Journal

  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 73(1), 41-50, 1997-01-01

    The Japanese Pharmacological Society

References:  27

Cited by:  5

Codes

  • NII Article ID (NAID)
    10008676832
  • NII NACSIS-CAT ID (NCID)
    AA00691188
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    00215198
  • NDL Article ID
    4131794
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  CJPref  NDL  J-STAGE 
Page Top