Abstract
Flutamide, a potent nonsteroidal antiandrogen, was administered orally to male beagle dogs for 2,3, or 4 years at doses of 10,20, or 40 mg/kg/day. At each study interval, the results of clinical pathology examinations, organ weight determinations, necropsy, and histopathologic examinations generally were similar and included atrophy of the prostate gland, testicular interstitial cell hyperplasia, and seminiferous tubular atrophy and degeneration. After 3 years of drug exposure, there were 3 dogs with testicular interstitial cell adenomas and a few dogs with 1 or more enlarged mammary gland nipples. Based upon the pharmacologic activity of flutamide, these findings were expected and considered the consequence of long-term blocking of testosterone receptors and an exaggerated compensatory response to increased secretion of luteinizing hormone. The findings of this study were consistent with other examples of dysregulated hormone stimulation of target tissues noted during the nonclinical safety assessment of flutamide. In consideration of the clinical indication of flutamide for advanced prostatic carcinoma and based upon reports of minimal flutamide-related adverse clinical responses, the findings of this study pose no concern for human risk assessment.