目的 总甘草素是甘草苷在体内的主要暴露形式，对两者在大鼠体内暴露特征及体外跨膜转运机制进行研究，为以甘草苷单体为新药的进一步开发提供依据。方法 采用LC-MS/MS分析方法测定大鼠给药后不同时间点血浆样品中的总甘草素浓度，并应用WinNonlin.6.3软件采用非房室模型的统计矩法计算药代动力学参数；同时测定大鼠ig给药后组织匀浆中的浓度，考察不同类型甘草素在各组织中的暴露特征；应用体外MDCK-MDR1细胞模型，研究甘草苷、甘草素的跨膜转运能力及其机制。结果 ig给药后在大鼠体内，甘草苷不呈线性动力学特征；血浆和大部分组织中主要以甘草素的II相结合产物存在，肝、子宫、卵巢、胃和肠组织中主要为游离甘草素；总甘草素暴露量排序为肠>血浆>肝>肾>肺>胃>子宫>卵巢>脂肪>心>脾>肌肉>睾丸，且不易产生组织蓄积现象；甘草素跨膜转运能力较甘草苷良好，且均不是P-gp转运体的底物。结论 甘草苷不呈线性动力学吸收特征；甘草素在组织中暴露特征表现为不同组织中甘草素的存在形式和分布程度差异较大，总甘草素不易产生组织蓄积现象；两者均为被动扩散跨膜转运方式。

Objective The total aglycone liquiritigenin represents the primary exposure of liquiritin in vivo in rats. The objective of this study was to investigate the characteristics of exposure and transport mechanism of liquiritin in vivo in rats and in vitro. The results could provide the evidence of liquiritin for its further development as a new drug. Methods The concentration of total aglycone liquiritigenin at different timing points in rat plasma and tissue distribution samples was determined by LC-MS/MS method after an oral administration of liquiritin in rats. The pharmacokinetic parameters were calculated by WinNonlin software using Rosenbluth method of non-compartment model. The exposure of total aglycone liquiritigenin and free liquiritigenin in rat tissues was investigated. And the transport mechanism of liquiritin and liquiritigenin was clarified using the MDCK-MDR1 cells in vitro. Results Liquiritin did not undergo linear pharmacokinetic characteristic after a single oral dose in rats. The phase II conjugation metabolites of liquiritigenin were the major exposure in plasma and most rat tissues. However, free liquiritigenin was primarily distributed in the tissue of rat liver, uterus, ovary, stomach and intestine. The exposure of total aglycone liquiritigenin in rat tissues did not show any accumulation trends. And the sequence of exposure was:intestine>plasma>liver>kidney>lung>stomach>uterus>ovary>fat>heart>spleen>muscle>testicle. The transport results indicated that both liquiritin and liquiritigenin were not the substrate of P-gp. And the transcellular transport of liquiritigenin from apical to basolateral membrane was higher than that of liquiritin in MDCK-MDR1 cells. Conclusion Liquiritin did not show linear pharmacokinetic characteristic after a single oral dose in rats. The characteristics of exposure of liquiritigenin in rat tissues indicated that the extent of distribution and type of liquiritigenin were different among tissues. The exposure of total aglycone liquiritigenin in rat tissues did not show any accumulation trends. The transcellular transport of liquiritin and liquiritigenin was mediated by passive diffusion.

R283

国家重点研发计划项目（2018YFC1708203）；中国医学科学院中央级公益性科研院所基本科研业务费专项资金资助（2018PT35031）；内蒙古自治区科技重大专项（2019ZD004）；天津市自然科学基金青年基金项目（20JCQNJC00320）