基于分子动力学的十二烷基硫酸钠对黄酮醇糖苷增溶作用及对体内药动学的影响

Influence of SDS on DF3G solubilizing behavior by molecular dynamics simulation and pharmacokinetics in vivo

目的通过分子动力学模拟黄酮醇糖苷(DF3G)在十二烷基硫酸钠(sodium dodecyl sulfate,SDS)水溶液中的增溶行为,通过HPLC-MS/MS法比较DF3G及DF3G的5%SDS水溶液(SDS-DF3G)的药动学差异。方法通过GROMACS软件与GROM OS 54A7联合原子力场进行分子动力学模拟。健康SD大鼠随机分为DF3G(60 mg/kg)和SDSDF3G(DF3G 60 mg/kg)2组,ig给药1次,于给药后0.25、0.50、0.75、1.00、1.50、2.00、4.00、6.00、8.00、10.00、24.00、30.00 h从SD大鼠眼眶后静脉丛取血,样品处理后,采用HPLC-MS/MS法测定血浆中DF3G的血药浓度。通过DAS2.0软件拟合计算药动学参数。结果分子动力学模拟结果显示,DF3G分子中苯环部分可以自发地增溶到胶束的疏水栅栏层,而其糖环中的羟基分别与2个SDS的硫酸基中的氧原子形成2个氢键,从而增加DF3G在水中的溶解性。与DF3G组比较,SDS-DF3G组AUC(0-t)、AUC(0-∞)增大,且具有显著性差异(P<0.05);CLz/F显著降低(P<0.05);Cmax升高,tmax、MRT延长,t1/2缩短。结论从理论上证实了添加表面活性剂可以对药物分子在胶束溶液中增溶,以期为该类体系的实验研究提供理论依据。从实验角度证实了加入SDS可以提高DF3G体内生物利用度。

Objective To explore the solubilization of DF3 G in SDS micelle by molecular dynamics software.To determine the concentration in rat plasma by HPLC-MS/MS of DF3 G,and to study the pharmacokinetics of DF3 G and SDS-DF3 G in rats.Methods Molecular dynamics simulation by GROMACS and Grom OS 54 A7 combined atomic force field for DF3 G and SDS.Rats were divided into DF3 G(60 mg/kg),SDS-DF3 G(60 mg/kg)groups.Blood samples were collected from inner canthus at 0.25,0.50,0.75,1.00,1.50,2.00,4.00,6.00,8.00,10.00,24.00,30.00 h.Samples were treated,and the concentrations of DF3 G were determined by HPLC-MS/MS.The pharmacokinetic parameters were calculated by DAS 2.0 Software.Results Molecular dynamics simulation showed that the benzene ring structure penetrates into the carbon chains of SDS,and the hydrophilic-OH groups of glucopyranoside formed two hydrogen-bond(H-bond)with oxygen atoms of the two SDS molecules respectively to form a better hydrophilic effect.Compared to DF3 G group,AUC(0-t)and AUC(0-∞)of SDS-DF3 G group increased,and had significant difference(P<0.05);CLZ/F was significantly decreased(P<0.05);Cmaxwas increased,tmaxand MRT were prolonged,t1/2 was shortened.Conlusion This work provided one convincing evidence that adding certain surfactants in water could effectively release the solubilization of some drugs,and thus give one helpful guidance for those corresponding experimental studies accordingly.The addition of SDS has the effect of increasing the absorption of DF3 G in vivo.