PHARMACOLOGICAL PROPERTIES OF YM17E, AN ACYL-COA-CHOLESTEROL ACYLTRANSFERASE INHIBITOR, AND DIARRHEAL EFFECT IN BEAGLE DOGS

YM17E tyl-3-(p-dimethylaminophenyl)ureido]methyl]benzene dihydrochlori de) was found to be a potent inhibitor of acyl-CoA:cholesterol acyltra nsferase (ACAT) in rabbit liver and intestine microsomes. Dixon plot a nalysis revealed that YM17E inhibited microsomal ACAT in a non-competi tive manner. YM17E induced a marked decrease in serum cholesterol, esp ecially in non-high-density lipoprotein (HDL) fractions, in cholestero l-fed rats and rats fed normal chow. Measurement of bile secretion aft er oral administration of YM17E in cholesterol-fed rats showed that th e drug markedly accelerated the secretion of bile acids and neutral st erols. Furthermore, absorption of [H-3]cholesterol from the gut of cho lesterol-fed rats was significantly inhibited by YM17E. From these res ults, the hypocholesterolemic activity of YM17E in these animals resul ted from both a decrease in cholesterol absorption from the gut and th e stimulation of excretion of cholesterol from the liver into bile. Ho wever, YM17E caused secretory diarrhea in beagle dogs at near lipid lo wering doses. When YM17E was administered at the same total dosage but divided into 5 daily administrations, the incidence of diarrhea was s ignificantly reduced while its cholesterol lowering effect became stro nger. These results suggest that the inhibition of intestinal and/or l iver ACAT increases the risk of diarrhea development which, however, c an be avoided by controlled drug administration in beagle dogs.