Single and Multiple Dose Pharmacokinetic Evaluation of Flutamide in Normal Geriatric Volunteers

Abstract

Single dose and steady-state pharmacokinetics of flutamide (F) and its active plasma metabolite, hydroxyflutamide (HF) were studied in twelve healthy geriatric volunteers administered 250 mg flutamide capsules on day 1 and 250 mg flutamide capsules three times a day on days 2 through 9. After oral administration, F was rapidly absorbed and metabolized. It was present in the plasma in small and variable concentrations, which precluded quantitative assessment of pharmacokinetic parameters for individual subjects. Steady-state plasma concentrations were reached on or before Day 6. The mean steady state Cmax (Day 9), 112.7 ng/ml, occurred at 1.3 hr. Pharmacokinetic analysis of mean data at steady-state gave a distribution and elimination half-life of 0.8 hr and 7.8 hours, respectively. The plasma levels for HF were much higher and less variable than F. The mean Cmax for HF averaged 894 ng/ml at 2.7 hours after a single dose and 1719 ng/ml (Day 9) at 1.9 hr after multiple doses. The distribution and elimination half-lives of HF at steady-state were 1.9 and 9.6 hours, respectively. The steady-state HF plasma concentrations were also achieved on or before Day 6 and were approximately twice those obtained after a single dose. From this study, it has been demonstrated that the pharmacokinetics of F and HF do not change appreciably upon multiple dosing of 250 mg F capsule given three times a day.

Metabolism and hepatic toxicity of flutamide in cytochrome P450 1A2 knockout SV129 mice

“…5,6 The exact metabolism of flutamide has not been fully demonstrated, but flutamide is also known to be metabolized into FLU-1 (4-nitro-3-(trifluoromethyl)phenylamine). 7,8 The plasma concentration of FLU-1 is usually much lower than that of OH-flutamide in clinical pharmacological examination, and it is metabolized further by hydroxylation and acetylation.…”

A Randomised Comparison of ‘Casodex’^TM (Bicalutamide) 150 mg Monotherapy versus Castration in the Treatment of Metastatic and Locally Advanced Prostate Cancer

“…‘Casodex’ (ICI 176,334) is a potent, non-steroidal anti-androgen that is absorbed orally, has a half life of approximately 1 week which allows once daily dosing [4] and has a higher affinity for the androgen receptor than other non-steroidal anti-androgens [5, 6]. This observed high affinity of non-steroidal anti-androgens for the androgen receptor has led to the theory that a potent anti-androgen such as ‘Casodex’ could effectively block the prostate androgen receptors and thereby eliminate the need for medical or surgical castration.…”

Ikterus und schwere Leberfunktionsst�rung bei der hormonablativen Behandlung des Prostatakarzinoms

“…[23]. Flutamid unterliegt einem hohen First-Pass-Metabolismus in den Enterozyten und in der Leber.Die beiden Hauptmetaboliten sind das biologisch aktive 2-Hydroxyflutamid und das 3-Trifluoromethyl-4-Nitroanilin.…”