Conversion and pharmacokinetics profiles of a novel pro-drug of 3-n-butylphthalide, potassium 2-(1-hydroxypentyl)-benzoate, in rats and dogs

• 来源期刊: 中国药理学报（英文版）
• 关键词: potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) pro-drug 3-n-butylphthalide (dl-NBP) ischemic stroke pharmacokinetics bioavailability
• 年，卷（期）: 2018,（2）
• 页码范围: 275-285
• 页数: 11页
• 语种: 英文
• DOI: 10.1038/aps.2017.90

摘要

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 Cmax 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.