Subacute toxicity of a novel inhibitor of acyl-CoA: cholesterol acyltransferase in beagle dogs.
PD 132301-2 is a substituted urea hypolipidemic and antiatherosclerotic agent that is a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT). To determine its subacute toxicity, PD 132301-2 was administered orally to beagle dogs at 0, 6, 12, 25, 50, 200, 400, or 800 mg/kg/day for 2 weeks. Clinico-pathologic evaluations were completed on all dogs. Liver and adrenal total and esterified cholesterol concentrations, adrenocorticotrophic hormone (ACTH) responsiveness, and adrenal ultrastructure were determined at 0, 6, 12, and 25 mg/kg. At 12 mg/kg or greater, salivation, epiphora, conjunctivitis, emesis, anorexia or decreased food consumption, and soft to mucoid feces and/or diarrhea were noted. Suppression of ACTH response occurred by Day 6 at all doses. Adrenocortical degeneration and/or necrosis in zona fasciculata and reticularis was seen at all doses; adrenal free and esterified cholesterol were normal at 6 mg/kg and decreased at 12 and 25 mg/kg. Increases in serum alanine aminotransferase (2- to 15-fold), aspartate aminotransferase (2- to 12-fold), and alkaline phosphatase (2- to 7-fold) were noted at 50 mg/kg or greater. Periportal hepatocellular hypertrophy and hypereosinophilia occurred at 50 mg/kg or greater; hepatic cholesterol values were not significantly affected by treatment. Dose-dependent ultrastructural alterations in adrenocortical cells included decreased numbers of mitochondria and smooth endoplasmic reticulum profiles, qualitative and quantitative changes in lipid globules, and increased numbers of autolysosomes. PD 132301-2 or one of its metabolites has potent adrenocorticolytic properties and limited hepatotoxic properties by mechanism(s) that are likely independent of systemic ACAT inhibition.
Dominick
M A
MA
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
McGuire
E J
EJ
Reindel
J F
JF
Bobrowski
W F
WF
Bocan
T M
TM
Gough
A W
AW
D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000187:drug effects; D000410:Alanine Transaminase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D001284:Atrophy / Q000139:chemically induced; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006400:Hematocrit; D006454:Hemoglobins / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects; D008297:Male; D008854:Microscopy, Electron; D009929:Organ Size / Q000187:drug effects; D010671:Phenylurea Compounds / Q000633:toxicity*; D012472:Salivation / Q000187:drug effects; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D015383:Zona Fasciculata / Q000473:pathology; D015385:Zona Reticularis / Q000473:pathology
D006454:Hemoglobins; D010671:Phenylurea Compounds; D000324:Adrenocorticotropic Hormone; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; C079534:N-(2,6-bis(1-methylethyl)phenyl)-N'-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride