Comparison of Nonclinical Toxicological Profiles Among PPAR Alpha, Gamma, and Delta Agonists

The nonclinical assessment of various peroxisome proliferator activated receptor (PPAR) agonists indicates that activation of the alpha, gamma, and/or delta receptors produces different toxicological effects. General PPAR-induced toxicities include effects on liver, heart, skeletal muscle, kidney, bladder, bone marrow, and carcinogenicity. PPAR alpha mediated effects in the liver include hypertrophy, peroxisome proliferation, necrosis, and hepatocellular proliferation. Peroxisome proliferation and liver tumors in rodents are believed to be species-specific, however peroxisome proliferation has been detected in non-rodents after administration of potent PPAR alpha agonists. Muscle degeneration (cardiac), bone marrow suppression, and kidney proximal tubule damage have also been associated with PPAR alpha activation. Compounds with PPAR gamma activity have produced cardiovascular toxicity secondary to fluid accumulation. These compounds produce edema which is associated with cardiac enlargement and congestive heart failure. Although overt liver toxicity was not identified as a dose-limiting toxicity in nonclinical studies, idiosyncratic liver toxicity lead to removal of a PPAR gamma agonist (troglitazone) from the market. PPAR gamma agonists have also been shown to produce changes in adipose tissue which may result in fatty infiltration of bone marrow. The toxicities associated with PPAR delta agonists are likely related to their intended pharmacological activity in muscle. PPAR delta agonists can produce myopathy in skeletal and cardiac muscle.