LC-MS/MS法研究甘草对雷公藤内酯酮药代动力学及组织分布与排泄的影响

目的:研究甘草对雷公藤内酯酮药代动力学及组织分布与排泄的影响,为阐明甘草对雷公藤的减毒作用机制奠定基础。方法:采用对比试验,将SD大鼠随机分为雷公藤内酯酮单独给药组和雷公藤内酯酮与甘草联合给药组,联合给药组提前灌服甘草后,分别尾静脉注射雷公藤内酯酮1.4mg·kg-1,采用LC-MS/MS法在选择离子监测(SIM)模式下测定雷公藤内酯酮单独给药和与甘草联合给药后不同时间大鼠血浆、组织液和排泄物中的雷公藤内酯酮浓度,比较单独和联合给药后雷公藤内酯酮药代动力学及组织分布与排泄的差异。结果:雷公藤内酯酮在测定范围内均呈良好线性关系(r0.99),日内和日间精密度RSD均小于15%,血浆中提取回收率均大于70%,各组织中提取回收率均大于60%,提取方法稳定可靠;单独给药和与甘草联合给药的药代动力学参数及组织分布与排泄均有明显差异。联合给药组的AUC与t1/2z明显小于单独给药组,而清除率(CL)则增大,说明联合给药组的代谢速度比单独给药组快;在组织分布中,单独给药组和联合给药组中雷公藤内酯酮均主要聚集于肺,联合给药组在组织中的分布浓度比单独给药组低;在排泄中,联合给药组中雷公藤内酯酮的排泄总量大于单独给药组约1倍。结论:甘草对雷公藤内酯酮药代动力学及组织分布与排泄均有显著影响,甘草可加速雷公藤内酯酮体内代谢与排泄,降低组织分布浓度,这可能与甘草降低雷公藤毒性有关。

Effect of Glycyrrhiza uralensis on Metabolism and Distribution and Excretion of Triptonide in vivo by LC-MS-MS

Objective: To study the effect of Glycyrrhiza uralensis on metabolism, distribution and excretion of triptonide in rat and disclose the attenuation mechanism of G. uralensis on triptonide in vivo. Method: The SD rats were divided into single and combined administration groups. The combined group was injected with triptonide after orally treated with extracts of Glycyrrhiza , while the single group was injected only with triptonide. The concentration of triptonide in plasma, tissue and excreta in vivo were determinated by LC-MS-MS method to compare with the difference of metabolism, distribution and excretion of triptonide under two administration models. Result: The determination methods with good precision and stability were suitable for the assay of triptonide in biological samples. The difference of metabolism, distribution and excretion of triptonide under single and combined administration models were significant. AUC and t_1/2Zof triptonide under combined administration model were decreasing, while CL was increasing compared with single administration model. The concentration of triptonide in tissue under combined administration model was decreasing, while excretion of triptonide was accelerated compared with single administration model. Triptonide was mainly distributed in the lung under two administration models. Conclusion: Glycyrrhiza can decrease the concentration of triptonide in tissue and accelerate the excretion of triptonide in rats. It may be one of the attenuation mechanisms of Glycyrrhiza on triptonide.