Transport, metabolism, and hepatotoxicity of flutamide, drug-drug interaction with acetaminophen involving phase I and phase II metabolites.

摘要: Treatment with flutamide has been associated clinical hepatotoxicty. The toxicity, metabolism,and transport of were investigated using cultured human hepatocytes. Flutamide and its major metabolite, 2-hydroxyflutamide, caused an inhibition taurocholate efflux in hepatocytes IC50=75 microM 110 microM, respectively. or 2-hydroxyflutamide for 24 h resulted time- concentration-dependent toxicity as assessed by protein synthesis. Toxicity was greater after 1 than treatment. Recovery synthesis attributed to the decreased presence due metabolism. metabolized several metabolites, formation reactive intermediates flutamide, evidenced glutathione-related adducts, observed. Inhibition metabolism 1-aminobenzotriazole (ABT) enhancement which sustained levels nonmetabolized drug. ABT also prevented flutamide. There additive when cells treated a combination 2-hydroxyflutamide. Simultaneous treatment acetaminophen (APAP) synergistic toxic effects. APAP found have significant effects on each other's inhibited glucuronidation sulfation APAP, resulting amounts available bioactivation. hydroxylation subsequent acetylation 4-nitro-3-(trifluoromethyl) aniline, metabolite In summary, we suggest that bile acid 2-hydroxy may play role flutamide-induced liver injury. Both are responsible cytotoxicity if not metabolized. data possible drug-drug interaction between increased bioactivation toxicity.