TY - JOUR AU - LI Jiang AU - XU Shao-feng AU - PENG Ying AU - FENG Nan AU - WANG Ling AU - WANG Xiao-liang PY - 2018 TI - Conversion and pharmacokinetics profiles of a novel pro-drug of 3- n -butylphthalide, potassium 2-(1-hydroxypentyl)-benzoate, in rats and dogs JF - Acta Pharmacologica Sinica; Vol 39, No 2 (February 2018): Acta Pharmacologica Sinica Y2 - 2018 KW - N2 - Abstract 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 max 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. UR - http://www.chinaphar.com/article/view/9726