Pharmacokinetics of BOF-4272, a xanthine oxidase inhibitor, after single intravenous or oral administration to male mice and rats.
BOF-4272, (+/-)-8-(3-methoxy-4-phenylsulphinylphenyl) pyrazolo [1,5-a]-1,3,5-triazine-4 (1H)-one), is a new drug intended for the treatment of hyperuricaemia. This report describes the detailed pharmacokinetics of BOF-4272 in mice and rats after intravenous or oral administration. Plasma concentrations of BOF-4272 at 2-8h after intravenous administration were significantly higher in mice than in rats. Plasma concentrations of BOF-4272 after oral administration were significantly higher in fed mice than in fasted mice, but were similar in fasted and fed rats. The elimination half-life of the distribution phase (t1/2(alpha)) was similar in mice (0.158 h) and rats (0.210 h). The elimination half-life of the terminal elimination phase (t1/2(beta)) in mice was 1.936 h, while that in rats was 0.742 h. The volume of the central compartment (V1) was almost the same in mice (415 mL kg(-1)) and rats (440 mL kg(-1)). However, the volume of the peripheral compartment (V2) in mice was 1068 mL kg(-1), while that in rats was 92 mL kg(-1). The steady-state volume of distribution (Vss) was 2.8 times larger in mice than in rats. The area under the plasma concentration-time curve (AUC) in mice was 5332 ng h mL(-1), while that in rats was 3806 ng h mL(-1). The AUC0-24 h after oral administration was 2.5 times greater in fed mice than in fasted mice, and was 1.4 times greater in fasted rats than in fed rats. The correlation coefficients of Cmax and AUC0-24 h in both mice and rats after oral administration were greater than 0.997 in the dose range 1 - 125 mg kg(-1), indicating that the linear range of absorption or elimination (or both) of BOF-4272 is very wide. The results of the present study demonstrate that the mouse is a suitable animal species for evaluating the clinical pharmacokinetics of BOF-4272.
Naito
S
S
Laboratory of Drug Metabolism Research, Naruto Research Institute, Otsuka Pharmaceutical Factory, Inc., Tokushima, Japan.
Nishimura
M
M
Nogawa
H
H
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D014227:Triazines / Q000493:pharmacokinetics*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D014227:Triazines; C072977:BOF 4272; D014969:Xanthine Oxidase