Synthesis, characterization and in vivo evaluation of honokiol bisphosphate prodrugs protects against rats’ brain ischemia-reperfusion injury

Publication date: Available online 15 December 2018Source: Asian Journal of Pharmaceutical SciencesAuthor(s): Gaojie Xu, Renghan Dong, Jin Liu, Li Zhao, Yan Zeng, Xiaofan Xiao, Jinlin An, Sheng Huang, Yueling Zhong, Bing Guang, Tai YangAbstractHonokiol (HK) usage is greatly restricted by its poor aqueous solubility and limited oral bioavailability. We synthesized and characterized a novel phosphate prodrug of honokiol (HKP) for in vitro and in vivo use. HKP greatly enhanced the aqueous solubility of HK (127.54 ± 15.53 mg/ml) and the stability in buffer solution was sufficient for intravenous administration. The enzymatic hydrolysis of HKP to HK was extremely rapid in vitro (T1/2 = 8.9 ± 2.11 s). Pharmacokinetics studies demonstrated that after intravenous administration of HKP (32 mg/kg), HKP was converted rapidly to HK with a time to reach the maximum plasma concentration of ∼5 min. The prodrug HKP achieved an improved T1/2 (7.97 ± 1.30 h) and terminal volume of distribution (26.02 ± 6.04 ml/kg) compared with direct injection of the equimolar parent drug (0.66 ± 0.01 h) and (2.90 ± 0.342 ml/kg), respectively. Furthermore, oral administration of HKP showed rapid and improved absorption compared with the parent drug. HKP was confirmed to maintain the bioactivity of the parent drug for ameliorating ischemia–reperfusion injury by decreasing brain infarction and improving neurologic function. Taken together, HKP is a potentially useful aqueous-soluble prodrug with i...
Source: Asian Journal of Pharmaceutical Sciences - Category: Drugs & Pharmacology Source Type: research