State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Acta Pharmacol Sin. 2018 Feb;39(2):275-285. doi: 10.1038/aps.2017.90. Epub 2017 Sep 14.
Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) is a novel pro-drug of 3-n-butylphthalide (dl-NBP) that is used to treat ischemic stroke. Currently, dl-PHPB is in phase II-III clinical trials in China. In this study, we investigated the conversion and pharmacokinetics profiles of dl-PHPB in vitro and in vivo. The conversion of dl-PHPB to dl-NBP was pH- and calcium-dependent, and paraoxonase was identified as a major enzyme for the conversion in rat plasma. The pharmacokinetics, tissue distribution and excretion of dl-PHPB were studied and compared with equal-molar doses of dl-NBP in rats and dogs. The in vivo studies showed that dl-PHPB could be quickly and completely converted to dl-NBP. The plasma concentration-time course of converted dl-NBP after intravenous dl-PHPB administration was nearly the same as that after equal-molar dl-NBP. The C and AUC of dl-NBP after oral dl-PHPB administration in rats and dogs were higher by 60% and 170%, respectively, than those after oral dl-NBP administration. Analysis of the tissue distribution of dl-PHPB revealed that converted dl-NBP was primarily distributed in fat, the brain and the stomach. In the brain, the levels of dl-NBP were relatively higher after dl-PHPB treatment by orally than after treatment with equal-molar dl-NBP. Approximately 3%-4% of dl-NBP was excreted within 72 h after dosing with dl-PHPB or dl-NBP, but no dl-PHPB was detected in urine or feces excrements. Our results demonstrate that the conversion of dl-PHPB is fast after oral or intravenous administration. Furthermore, the bioavailability of dl-PHPB was obviously better than that of dl-NBP.
2-(1-羟基戊基)苯甲酸钾（dl-PHPB）是一种新型的 3-正丁基苯酞（dl-NBP）前药，用于治疗缺血性脑卒中。目前，dl-PHPB 正在中国进行 II-III 期临床试验。在这项研究中，我们研究了 dl-PHPB 在体外和体内的转化和药代动力学特征。dl-PHPB 转化为 dl-NBP 是 pH 和钙依赖性的，并且对氧磷酶被鉴定为大鼠血浆中转化的主要酶。研究了 dl-PHPB 的药代动力学、组织分布和排泄，并在大鼠和狗中与等摩尔剂量的 dl-NBP 进行了比较。体内研究表明，dl-PHPB 可以快速而完全地转化为 dl-NBP。静脉给予 dl-PHPB 后转化的 dl-NBP 的血浆浓度-时间曲线与等摩尔 dl-NBP 给药后几乎相同。大鼠和狗口服 dl-PHPB 后 dl-NBP 的 C 和 AUC 分别比口服 dl-NBP 高 60%和 170%。对 dl-PHPB 组织分布的分析表明，转化的 dl-NBP 主要分布在脂肪、大脑和胃中。在大脑中，口服 dl-PHPB 处理后 dl-NBP 的水平相对高于等摩尔 dl-NBP 处理后。口服 dl-PHPB 或 dl-NBP 后 72 小时内约有 3%-4%的 dl-NBP 被排泄，但尿液或粪便排泄物中未检测到 dl-PHPB。我们的结果表明，dl-PHPB 经口服或静脉给药后转化迅速。此外，dl-PHPB 的生物利用度明显优于 dl-NBP。
