Preclinical toxicology studies with the lipid-regulating agent gemcadiol.
Gemcadiol is a medium-length diol moiety with lipid-regulating properties in animals and man. The compound was not toxic when single doses were administered to rodents with the lethal dose greater than 7000 mg/kg in rats and mice. Rats treated for 13 or 52 weeks with 30 to 300 mg/kg had reversible food intake suppression and weight gain inhibition, decreased blood cholesterol, slight anemia, and generally dose-related but reversible decreases in glucose, and increases in alkaline phosphatase and blood urea nitrogen. Liver weights were increased, and there was accompanying hypertrophy and increased cytoplasmic eosinophilia of hepatocytes with associated peroxisome proliferation. Rats treated for 52 weeks also had mild renal tubular dilatation. Dogs given 25 to 300 mg/kg of gemcadiol for up to 52 weeks tolerated the compound better than rats. Effects related to compound administration were elevated serum alanine aminotransferase activity in female animals only, and microscopic cytoplasmic vacuolation and hyaline body formation in both sexes. Monkeys given 25 to 300 mg/kg gemcadiol for 13 weeks had slightly decreased serum cholesterol and slightly increased serum creatine phosphokinase. Teratology studies in rats or rabbits indicated no teratogenic response. Gemcadiol affects principally the liver, and the hepatic alterations seen in rats and dogs may reflect compensatory manifestations of altered metabolism related to the lipid-regulating activity of the compound.
J E
JE
Fitzgerald
J A
JA
Petrere
E J
EJ
McGuire
F A
FA
de la Iglesia
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D001769:Blood / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000002:abnormalities; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005233:Fatty Alcohols / Q000633:toxicity*; D005260:Female; D000960:Hypolipidemic Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D005233:Fatty Alcohols; D000960:Hypolipidemic Agents; C014003:gemcadiol