摘要
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±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(T 1/2=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 T 1/2(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 improved pharmacokinetic properties which may merit further development as a potential drug candidate.
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 ± 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 improved pharmacokinetic properties which may merit further development as a potential drug candidate.
基金
supported by the Scientific Research Fund of the National Natural Science Foundation of China ( 81201668 )
Chengdu Science and Technology Bureau ( 2015HM01-00506-SF , 2018-YF05-00454-SN )
Scientific Research Fund of the Sichuan Provincial Education Department (17CZ0011, 17ZA0109)
the Scientific Research Fund of Chengdu Medical College (CYCG15-01)
