Flutamide-induced hepatic dysfunction in relation to steady-state plasma concentrations of flutamide and its metabolites.
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.
Aizawa
Yoshio
Y
Department of Internal Medicine, Jikei University School of Medicine, Aoto Hospital, Tokyo, Japan. y-aizawa@qa2.so-net.ne.jp
Ikemoto
Isao
I
Kishimoto
Koichi
K
Wada
Tetsuro
T
Yamazaki
Haruki
H
Ohishi
Yukihiko
Y
Kiyota
Hiroshi
H
Furuta
Nozomu
N
Suzuki
Hidenori
H
Ueda
Masataka
M
D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000009:adverse effects* / Q000097:blood* / Q000627:therapeutic use; D005485:Flutamide / Q000009:adverse effects* / Q000097:blood* / Q000627:therapeutic use; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology
D000726:Androgen Antagonists; D005485:Flutamide