Biopharmaceutical, preclinical pharmacokinetic and pharmaco-dynamic investigations of an orally administered novel 3-nbutylphthalide prodrug for ischemic stroke treatment

Ischemic stroke (IS) has been contributing in leading causes of disability and death worldwide and the cases are still increasing. In China, naturally sourced compound 3-n-butylphthalide (NBP) is widely applied in clinical practice for IS treatment with established evidences of efficacy and safety. However, NBP is an oily liquid at room temperature and has no active brain targeting ability, quite limiting its broader application in clinical practice. Via intravenous injection (i.v.) a prodrug compound (DB1) we previously developed deriving from NBP had dramatically enhanced the pharmacological effects, where however, this i.v. route still discount future patient compliance. As druggability of DB1 in oral administration has yet to be elaborated, the current study intended to systemically investigate its biopharmaceutical properties, so as to further consider clinical applicability of DB1 oral preparations. Additionally, pharmacokinetics and pharmacodynamics of DB1 via oral administered route were also studied, illustrating broad potential of further DB1 medicine development. After the derivation, aqueous solubility of DB1 improved 3∼400 folds compared with NBP in various pH media, and n-octanol/water partition coefficient kept in the range of 0∼2. In situ single-pass intestinal perfusion on rats showed effective permeability coefficient of DB1 over 10-2 cm/s. In contrast to NBP, oral administration of DB1 could display significant enhanced bioavailability in rats and achieve increased accumulation in brain tissues. As expected, DB1 effectively alleviated oxidative stress damage and reduced infarct volume on ischemia/reperfusion (I/R) modeled rats, resulting in reduced mortality. Additionally, this new prodrug did not add any safety concerns based on NBP. Therefore, biopharmaceutical results and preclinical pharmacodynamic evidences support the conclusion that an oral administration of DB1 may have a good potential for clinical IS treatment. [Display omitted]