Naito S, Nishimura M, Nogawa H
Laboratory of Drug Metabolism Research, Naruto Research Institute, Otsuka Pharmaceutical Factory, Inc., Tokushima, Japan.
J Pharm Pharmacol. 1999 Mar;51(3):347-51. doi: 10.1211/0022357991772358.
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.
BOF-4272，即（±）-8-（3-甲氧基-4-苯基亚磺酰基苯基）吡唑并[1,5-a]-1,3,5-三嗪-4（1H）-酮，是一种用于治疗高尿酸血症的新药。本报告描述了静脉注射或口服给药后BOF-4272在小鼠和大鼠体内的详细药代动力学情况。静脉注射后2至8小时，小鼠体内BOF-4272的血浆浓度显著高于大鼠。口服给药后，喂食小鼠体内BOF-4272的血浆浓度显著高于禁食小鼠，但禁食和喂食大鼠体内的血浆浓度相似。分布相的消除半衰期（t1/2(α)）在小鼠（0.158小时）和大鼠（0.210小时）中相似。小鼠终末消除相的消除半衰期（t1/2(β)）为1.936小时，而大鼠为0.742小时。中央室容积（V1）在小鼠（415 mL kg(-1)）和大鼠（440 mL kg(-1)）中几乎相同。然而，小鼠外周室容积（V2）为1068 mL kg(-1)，而大鼠为92 mL kg(-1)。稳态分布容积（Vss）在小鼠中比大鼠大2.8倍。小鼠血浆浓度-时间曲线下面积（AUC）为5332 ng h mL(-1)，而大鼠为3806 ng h mL(-1)。口服给药后，喂食小鼠的AUC0-24 h比禁食小鼠大2.5倍，禁食大鼠的AUC0-24 h比喂食大鼠大1.4倍。在1至125 mg kg(-1)剂量范围内，小鼠和大鼠口服给药后的Cmax与AUC0-24 h的相关系数均大于0.997，表明BOF-4272的吸收或消除（或两者）线性范围非常宽。本研究结果表明，小鼠是评估BOF-4272临床药代动力学的合适动物物种。
