Jpn. J. Pharmacol. 73 (1), 41-50 (1997)
Pharmacological Properties of YM17E, an Acyl-CoA:Cholesterol Acyltransferase
Inhibitor, and Diarrheal Effect in Beagle Dogs
Makoto Kashiwa (1), Yoichi Masuyama (1), Hiromi Miyauchi (1), Taisuke Uchida
(2), Shin Naganuma (1), Hirotoshi Kakuta (1), Motoko Terada (1), Takashi
Kiriyama (1), Koyo Matsuda (1), Noriki Ito (1), Yuichi Iizumi (1) and Toichi
Takenaka (1)
(1) Cardiovascular and Atherosclerosis Research Laboratories, Yamanouchi
Institute for Drug Discovery Research, 21 Miyukigaoka, Tsukuba, Ibaraki
305, Japan
(2) Drug Metabolism Department, Yamanouchi Pharmaceutical Co., Ltd., 1-8,
Azusawa 1-chome, Itabashi-ku, Tokyo 174, Japan
Abstract: YM17E (1,3-bis[[1-cycloheptyl-3-(p-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-high-density 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 [3H]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.
Keywords: YM17E, Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor,
Cholesterol, Diarrhea
Copyright© The Japanese Pharmacological Society 1997
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