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

作　　者：Jiang LI Shao-feng XU Ying PENG Nan FENG Ling WANG Xiao-liang WANG 

机构地区：[1]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

出　　处：《Acta Pharmacologica Sinica》2018年第2期275-285,共11页中国药理学报（英文版）

摘　　要：Potassium 2-（1-hydroxypentyl）-benzoate （d/-PHPB） is a novel pro-drug of 3-n-butylphthalide （dkNBP） 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 dI-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 dI-NBP after intravenous dl-PHPB administration was nearly the same as that after equal-molar dl-NBR The Cmax and AUC of d/-NBP after oral d/-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-NBR 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.Potassium 2-（1-hydroxypentyl）-benzoate （d/-PHPB） is a novel pro-drug of 3-n-butylphthalide （dkNBP） 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 dI-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 dI-NBP after intravenous dl-PHPB administration was nearly the same as that after equal-molar dl-NBR The Cmax and AUC of d/-NBP after oral d/-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-NBR 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.

关 键 词：potassium 2-（1-hydroxypentyl）-benzoate （dl-PHPB） PRO-DRUG 3-n-butylphthalide （dFNBP） ischemic stroke PHARMACOKINETICS bioavailability 

分 类 号：Q959.837[生物学—动物学] I207.42[文学—中国文学]