ABSTRACT
Honokiol (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⯱â¯15.53â¯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 â¯=â¯8.9⯱â¯2.11â¯s). Pharmacokinetics studies demonstrated that after intravenous administration of HKP (32â¯mg/kg), HKP was converted rapidly to HK with a time to reach the maximum plasma concentration of â¼5â¯min. The prodrug HKP achieved an improved T1/2 (7.97⯱â¯1.30â¯h) and terminal volume of distribution (26.02⯱â¯6.04â¯ml/kg) compared with direct injection of the equimolar parent drug (0.66⯱â¯0.01â¯h) and (2.90⯱â¯0.342â¯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 improved pharmacokinetic properties which may merit further development as a potential drug candidate.