Naito S, Nishimura M, Tamao Y
Laboratory of Drug Metabolism Research, Naruto Research Institute, Otsuka Pharmaceutical Factor, Inc., Tokushima, Japan.
J Pharm Pharmacol. 2000 Feb;52(2):173-9. doi: 10.1211/0022357001773823.
BOF-4272 (+/-)-8-(3-methoxy-4-phenylsulphinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4-(1H)-one, a new synthetic anti-hyperuricaemic drug, which has a chiral centre and exists as racemates, is a potent inhibitor of xanthine oxidase/dehydrogenase in the purine catabolism pathways. The present studies using mice demonstrated that BOF-4272 was specifically distributed in the liver, which is the main organ of uric acid production. Therefore, a decrease in uric acid concentration in the liver, rather than the plasma, was identified as a pharmacological action of BOF-4272. The ratio of liver to plasma concentrations of BOF-4272 increased from 2.5 to 6.3 over time, up to 8 h after oral administration. The elimination half-life of BOF-4272 in the liver was 5-1-fold longer than that in the plasma. High concentrations of BOF-4272 were observed in the liver up to 8 h after oral administration. Furthermore, the influx of BOF-4272 into hepatocytes occurred in a temperature-dependent manner. The liver concentrations of uric acid from 1 h to 8 h after the oral administration of BOF-4272 (0.34-0.75 microg (g tissue)(-1)) were significantly lower than those in control animals (5.03-10.96 microg (g tissue)(-1)). BOF-4269 (the sulphide metabolite of BOF-4272) was the only metabolite detected in plasma or faeces after intravenous or oral administration. BOF-4269, which has no inhibitory action on the uric acid biosynthesis system, is generated by the metabolism of BOF-4272 in the intestinal tract. In conclusion, this work using the liver as the target organ has allowed us to identify the pharmacological actions of BOF-4272 in mice. The long-lasting effect of BOF-4272 in reducing levels of hepatic uric acid was consistent with the prolonged high BOF-4272 concentrations in the liver. These results also demonstrate that the mouse is a suitable animal species for evaluating the clinical pharmacology and 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，是一种新型合成抗高尿酸血症药物，它有一个手性中心，以消旋体形式存在，是嘌呤分解代谢途径中黄嘌呤氧化酶/脱氢酶的强效抑制剂。目前用小鼠进行的研究表明，BOF-4272特异性分布于肝脏，而肝脏是尿酸生成的主要器官。因此，肝脏中尿酸浓度的降低而非血浆中尿酸浓度的降低被确定为BOF-4272的药理作用。口服给药后长达8小时，BOF-4272的肝脏与血浆浓度比从2.5增至6.3。BOF-4272在肝脏中的消除半衰期比在血浆中长5至1倍。口服给药后长达8小时，肝脏中均观察到高浓度的BOF-4272。此外，BOF-4272流入肝细胞的过程呈温度依赖性。口服BOF-4272（0.34 - 0.75微克/（克组织）⁻¹）后1至8小时，肝脏中的尿酸浓度显著低于对照动物（5.03 - 10.96微克/（克组织）⁻¹）。BOF-4269（BOF-4272的硫化物代谢产物）是静脉注射或口服给药后在血浆或粪便中检测到的唯一代谢产物。BOF-4269对尿酸生物合成系统无抑制作用，它是BOF-4272在肠道中代谢产生的。总之，这项以肝脏为靶器官的研究使我们能够确定BOF-4272在小鼠体内的药理作用。BOF-4272在降低肝脏尿酸水平方面的持久作用与肝脏中BOF-4272长时间保持高浓度一致。这些结果还表明，小鼠是评估BOF-4272临床药理学和药代动力学的合适动物物种。
