On Brain targeting research of ginkgolide B prodrug / 中国药理学通报

ABSTRACT

Aim To investigate the brain targeting of ginkgolide B prodrug (PGB ) and its mechanism. Methods The liquid chromatography tandem mass spectrometry (LC-MS /MS)method was applied to in-vestigate the pharmacokinetics of PGB in rat brain tis-sue after intravenous injection of PGB.Also the brain targeting was evaluated on the basis of the pharmacoki-netic parameter of PGB.The incomplete cerebral is-chemia model was induced in mouse,the effect of PGB on cerebral capillary permeability was observed by Ev-ans blue method.High performance liquid chromatog-raphy (HPLC)was used to determine the partition co-efficients (logP)of PGB in octanol-water system.PGB and P-glycoprotein (P-gp)was docked by using Mole-gro Virtual Docker (MVD)software to predict its bind-ing abilities with P-gp.The interaction of PGB with ATPase activity of human P-gp membrane was esti-mated by measuring inorganic phosphate liberation. Results The brain targeting of PGB was evaluated by treatment effective (TA ) and drug targeting index (DTI),the calculated value were 6.87 and 4.1 4 re-spectively.Preventive medication of PGB could signifi-cantly decrease cerebral capillary permeability (P <0.05).The lipo-hydropartition coefficient of PGB was higher than that of GB,their logP data were 1 .03 and 0.61 respectively.PGB displayed the stronger binding affinity with P-gp than GB according to the molecular docking calculations,their MolDock Score toward P-gp were -1 43.36 and -1 1 6.40KJ·mol -1 respectively. ATP-hydrolisis showed that PGB increased ATPase activity with a Km of approximately 237.75 μmol · L -1 ,however GB with a Km of approximately 841 .24μmol·L -1 .PGB might interact with P-gp with a high-er affinity and exhibit more effect than GB.Conclu-sion PGB is characterized by its brain targeting. Higher liposolubility of PGB results in good blood-brain permeability,which is advantageous to its brain targe-ting.Besides,PGB can effectively inhibit the efflux effect of P-gp to GB because of its increased P-gp AT-Pase activity.