Hepatic and Adrenal Toxicity of a Novel Lipid Regulator in Beagle Dogs

PD 138142-15 is a substituted urea hypolipidemic and potentialanti-atherosclerotic agent. To determine the toxicity of PD138142-15, beagle dogs were given oral doses of 1, 10, 30, and100 mg/kg daily for 13 weeks. Two animals at 100 mg/kg wereeuthanized during Week 5 due to poor condition. Clinical findingsincluded decreased serum albumin at mg/kg, and increased ALP(up to 30-fold) and 5'-nucleotidase activities (up to 9-fold)at doses 10 mg/kg. ALT and AST activities were elevated onlyat 100 mg/kg. There was a two- to threefold increase in cytochromeP450 content of hepatic microsomes from all treated animalsand increases in liver weights at 10 mg/kg and above. Hepaticchanges included hepatocellular hypertrophy and increased cytoplasmiceosinophilia at 10 mg/kg; single cell necrosis of hepatocyteswas noted in moribund animals. ACTH-stimulated cortisol levelswere decreased at 30 and 100 mg/kg. Adrenal cholesterol esterswere decreased at 10 mg/kg and above, while total adrenal cholesterolwas decreased at 30 mg/kg. These changes correlated with adrenalcortical zonal atrophy, principally of the zona fasciculataand zona reticularis, present at 30 and 100 mg/kg. Plasma concentrationsof PD 138142-15 increased with increasing dose; plasma levelswere significantly lower during Week 12 than those on Day 1,possibly due to autoinduction. Overt hepatotoxicity occurredat 100 mg/kg, whereas hepatic changes at 10 and 30 mg/kg wereconsistent with cytochrome P450 induction. The hepatic lesionswere reversible within 4 weeks, while adrenal lesions were stillevident after 4 weeks without treatment.