ABSTRACT
The toxicological profile of bicalutamide in animals following acute and chronic dosing is closely associated with the drug's non-steroidal anti-androgenic pharmacological activity. Bicalutamide produces typical effects of an anti-androgen, including atrophy of the prostate, testis and seminal vesicles and Leydig cell hyperplasia resulting from inhibition of pituitary feedback by testosterone. Subsequent benign Leydig cell tumors were seen in rats, but Leydig cell hyperplasia has not been observed in patients. Bicalutamide causes liver enlargement and is a mixed function oxidase inducer in rodents and dogs, but not man. These effects lead to thyroid hypertrophy and adenoma in the rat and hepatocellular carcinoma in the male mouse. In vitro and in vivo genotoxicity studies have all given negative results. Bicalutamide also caused a reversible shortening of the electrocardiographic P-R interval in the dog without any associated pathology. This change was not detected in ECG monitoring during clinical trials. In conclusion, bicalutamide produced a range of pharmacological effects, as well as liver enlargement with enzyme induction and dog ECG changes in preclinical toxicity studies in rodents and dogs. Only the pharmacological changes were found to be relevant to human usage.
Subject(s)
Androgen Antagonists/toxicity , Anilides/toxicity , Receptors, Androgen/metabolism , Animals , Body Weight/drug effects , Dogs , Dose-Response Relationship, Drug , Electrocardiography/drug effects , Female , Humans , Liver/drug effects , Liver/enzymology , Male , Mice , Mutagenicity Tests , Nitriles , Ovary/drug effects , Ovary/metabolism , Prostate/drug effects , Prostate/metabolism , Rats , Reproduction/drug effects , Seminal Vesicles/drug effects , Seminal Vesicles/metabolism , Testis/drug effects , Testis/metabolism , Testosterone/metabolism , Tosyl Compounds , Uterus/drug effects , Uterus/metabolismABSTRACT
Autoradiography was used to study the distribution of 2,2'-14C-methylene-bis-(3,4,6-trichlorophenol) (HCP) in pregnant marmoset monkeys in early (day 30-50) and late (around day 120) gestation and in a newborn (11 days old) pup. Radioactivity was present in the conceptus at all stages of gestation, although the foetal concentration was lower than the maternal. In the embryo an accumulation was observed in the neural tube and in the embryonic membranes. In the late foetus and newborn monkey the highest concentration of radioactivity was found in the liver and the intestinal contents. The brain of the adult and newborn animals showed low concentration. A partial blood-brain barrier was present in the late foetus but, in relation to other tissues, the foetal brain concentration was higher than that of the mother.