Pharmacokinetics of flutamide and its metabolite 2-hydroxyflutamide in normal and hepatic injury rats.
OBJECTIVE
To develop a new HPLC assay to study the pharmacokinetics of flutamide (Flu) and its active metabolite 2-hydroxyflutamide (HF) in rats.


METHODS
Normal or hepatic injury rats were given i.g. Flu 50 mg.kg-1. Reverse phase HPLC was developed with a mu-Bondapak C 18 column. Internal standard was methyltestosterone. The mobile phase was a mixture of methanol:acetonitrile:water:diethyl ether = 40:20:35:1 (vol). Absorbance was measured at lambda 234 nm.


RESULTS
The pharmacokinetic parameters of Flu were as follows: in normal rats, K = 0.62 +/- 0.16 h-1, Cl = 6.0 +/- 1.0 L.kg-1.h-1, AUC = 8.6 +/- 1.3 mg.L-1.h, Cmax = 2.4 +/- 0.7 mg.L-1; in hepatic injury rats, K = 0.16 +/- 0.03 h-1, Cl = 0.63 +/- 0.29 L.kg-1.h-1, AUC = 100 +/- 44 mg.L-1.h, Cmax = 6.7 +/- 2.8 mg.L-1. The pharmacokinetic parameters of HF were as follows: in normal rats, K(m) = 0.07 +/- 0.01 h-1, AUC = 219 +/- 22 mg.L-1.h, Cmax = 8.6 +/- 0.6 mg.L-1; in hepatic injury rats, K(m) = 0.05 +/- 0.01 h-1, AUC = 170 +/- 42 mg.L-1.h, Cmax = 3.8 +/- 0.8 mg.L-1. There were significant differences between the parameters of normal and hepatic injury rats (P < 0.01) except AUC of HF (P > 0.05).


CONCLUSIONS
This HPLC assay was sensitive and precise, and the elimination of Flu and HF was inhibited significantly due to hepatic injury.
Xu
C J
CJ
Department of Pharmacology, School of Pharmacy, Shanghai Medical University, China.
Li
D
D
D000726:Androgen Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D002252:Carbon Tetrachloride Poisoning; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005485:Flutamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000726:Androgen Antagonists; C014290:hydroxyflutamide; D005485:Flutamide