Hepatic and adrenal toxicity of a novel lipid regulator in beagle dogs.
PD 138142-15 is a substituted urea hypolipidemic and potential anti-atherosclerotic agent. To determine the toxicity of PD 138142-15, beagle dogs were given oral doses of 1, 10, 30, and 100 mg/kg daily for 13 weeks. Two animals at 100 mg/kg were euthanized during Week 5 due to poor condition. Clinical findings included decreased serum albumin at > or = 30 mg/kg, and increased ALP (up to 30-fold) and 5'-nucleotidase activities (up to 9-fold) at doses > or = 10 mg/kg. ALT and AST activities were elevated only at 100 mg/kg. There was a two- to threefold increase in cytochrome P450 content of hepatic microsomes from all treated animals and increases in liver weights at 10 mg/kg and above. Hepatic changes included hepatocellular hypertrophy and increased cytoplasmic eosinophilia at > or = 10 mg/kg; single cell necrosis of hepatocytes was noted in moribund animals. ACTH-stimulated cortisol levels were decreased at 30 and 100 mg/kg. Adrenal cholesterol esters were decreased at 10 mg/kg and above, while total adrenal cholesterol was decreased at > or = 30 mg/kg. These changes correlated with adrenal cortical zonal atrophy, principally of the zona fasciculata and zona reticularis, present at 30 and 100 mg/kg. Plasma concentrations of PD 131842-15 increased with increasing dose; plasma levels were significantly lower during Week 12 than those on Day 1, possibly due to autoinduction. Overt hepatotoxicity occurred at 100 mg/kg, whereas hepatic changes at 10 and 30 mg/kg were consistent with cytochrome P450 induction. The hepatic lesions were reversible within 4 weeks, while adrenal lesions were still evident after 4 weeks without treatment.
Wolfgang
G H
GH
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Warner Lambert Company, Ann Arbor, Michigan 48105, USA.
Robertson
D G
DG
Welty
D F
DF
Metz
A L
AL
D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D002219:Carbamates / Q000097:blood / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D005260:Female; D000960:Hypolipidemic Agents / Q000097:blood / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D002219:Carbamates; D000960:Hypolipidemic Agents; C086204:((2,6-bis(1-methylethyl)phenoxy)sulfonyl)carbamic acid 2,6-bis(1-methylethyl)phenyl ester; D003577:Cytochrome P-450 Enzyme System; D002785:Sterol O-Acyltransferase