Antitumor Activity And Pharmacokinetic Study Of 28-O-succinyl Betulin In Rat Plasma

28-O-succinyl betulin(B17),which was synthesized from betulin and succinyl oxide,showed good antitumor activity in vitro.In further studies on B17 were investigated including the in vivo antitumor activity,the UPLC-MS/MS method for the quantification of B17,and the pharmacokinetic study in rat plasma.Equilibrium solubility and apparent oil/water partition coefficients of B17 were measured by a HPLC method.The results showed that both of the parameters are related to the solvent polarity and the pH of matrix.The maximum equilibrium solubility in n-butyl alcohol and phosphate buffer(Ph=7.4)were 7187.00 mg/L and 29.78 mg/L,respectively.The oil/water partition coefficients in phosphate buffer(Ph=7.4)was 8.14(LgP=0.91).To elucidate the in vivo anti-cancer activity of B17,the Lewis lung carcinoma cells were transplanted into the C57BL/6J mice.The mice were treated with B17 and betulinic acid(the positive control).The result shows that the in vivo anti-cancer activity of B17 is better than betulinic acid.A UPLC-ESI/MS/MS method was developed and validated for the quantification of B17 in rat plasma.Samples were separated on an ACQ UPLC BEH C18 column which was equilibrated and gradient eluted with acetonitrile and water(5 mmol/L ammonium acetate)at a flow rate of 0.25 mL/min.The detection was performed in negative ion mode by multiple reactions monitoring(MRM).The precursor/product transitions(m/z)541.6?98.9 and 181.1?93.0 were used for the quantification of B17 and 2-Hydroxyethyl salicylate(the internal standard).The precision,accuracy,stability and recovery were within an acceptable range,which proved the method was sensitive,selective and accurate.The UPLC-MS/MS method was applied to the pharmacokinetic study of B17 in rat plasma.The results showed that after i.g.administration at a dose of 200 mg/kg,the concentration of drug reached the maximum value at four hours,after i.v.administration at a dose of 5 mg/kg of B17,the concentration of drug reached the maximum immediately.The drug was declined slowly and almost cleared all at 48 hours for both administrations.The oral bioavailability in rat was 9.49%by comparing the different administrations and laying a foundation for the future development.