Flutamide-induced hepatic dysfunction in relation to steady-state plasma concentrations of flutamide and its metabolites

Mol Cell Biochem. 2003 Oct;252(1-2):149-56. doi: 10.1023/a:1025560513308.


The frequency, severity, and outcome of flutamide-induced hepatic injury were prospectively evaluated in 55 patients with prostate cancer who received 125 mg of flutamide 3 times a day (daily dose: 375 mg) combined with an agonistic analogue of luteinizing hormone-releasing hormone. In addition, we examined plasma and urine concentrations of flutamide and its major metabolites 4 weeks after the beginning of flutamide therapy, and evaluated their significance in predicting flutamide-induced hepatic dysfunction. Hepatic function could be assessed in 50 patients and hepatic dysfunction during therapy was observed in 9 patients (18%); 3 patients (6%) were classified as having moderate liver dysfunction and 6 (12%) were classified as having mild liver dysfunction. The steady-state plasma levels of flutamide and its biologic active metabolite, hydroxyflutamide (OH-Flu), were not related to hepatic dysfunction. However, the concentration of another major metabolite, 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) was considerably higher in 2 patients who developed clinically significant hepatic dysfunction. These findings suggest that clinically significant hepatic dysfunction could be induced in patients with compromised flutamide metabolism, which leads to a high concentration of FLU-1. Based on results of this study, we propose that plasma FLU-1 levels are one of the predictive factors for flutamide-induced hepatic dysfunction. This hypothesis will be confirmed in a large-scale study.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Androgen Antagonists / adverse effects*
  • Androgen Antagonists / blood*
  • Androgen Antagonists / therapeutic use
  • Flutamide / adverse effects*
  • Flutamide / blood*
  • Flutamide / therapeutic use
  • Humans
  • Liver / drug effects*
  • Liver / physiopathology
  • Male
  • Middle Aged
  • Prospective Studies
  • Prostatic Neoplasms / blood
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / physiopathology


  • Androgen Antagonists
  • Flutamide