HEPATIC AND ADRENAL TOXICITY OF A NOVEL LIPID REGULATOR IN BEAGLE DOGS

PD 138142-15 is a substituted urea hypolipidemic and potential anti-at herosclerotic 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 w eeks. Two animals at 100 mg/kg were euthanized during Week 5 due to po or condition, Clinical findings included decreased serum albumin at gr eater than or equal to 30 mg/kg, and increased ALP (up to 30-fold) and 5'-nucleotidase activities (up to 9-fold) at doses greater than or eq ual to 10 mg/kg, ALT and AST activities were elevated only at 100 mg/k g. There was a two- to threefold increase in cytochrome P450 content o f hepatic microsomes from all treated animals and increases in liver w eights at 10 mg/kg and above. Hepatic changes included hepatocellular hypertrophy and increased cytoplasmic eosinophilia at greater than or equal to 10 mg/kg; single cell necrosis of hepatocytes was noted in mo ribund animals, ACTH-stimulated cortisol levels were decreased at 30 a nd 100 mg/kg, Adrenal cholesterol esters were decreased at 10 mg/kg an d above, while total adrenal cholesterol was decreased at greater than or equal to 30 mg/kg, These changes correlated with adrenal cortical zonal atrophy, principally of the zona fasciculata and zona reticulari s, present at 30 and 100 mg/kg. Plasma concentrations of PD 138142-15 increased with increasing dose; plasma levels were significantly lower during Week 12 than those on Day 1, possibly due to autoinduction. Ov ert hepatotoxicity occurred at 100 mg/kg, whereas hepatic changes at 1 0 and 30 mg/kg were consistent with cytochrome P450 induction, The hep atic lesions were reversible within 4 weeks, while adrenal lesions wer e still evident after 4 weeks without treatment. (C) 1995 Society of T oxicology.