大黄素甲醚大鼠体内毒代动力学研究

Toxicokinetics Study of Physcion in Rats in Vivo

目的建立用于血浆中大黄素甲醚及其代谢产物含量测定的超高效三重四级杆质谱联用(UPLC-QTOF-MS)方法,研究其原型及代谢产物大鼠体内毒代动力学(TK)行为。方法开展重复给药毒性试验的首次给药至给药结束的原型及其代谢产物的TK测定,计算动力学参数,评价大鼠口服不同剂量的大黄素甲醚后大鼠血浆中原型及代谢产物的暴露程度。结果研究发现首末次给药后原型及代谢产物的血浆暴露量与给药剂量无剂量依存关系,3个给药剂量下,大黄素甲醚在体内ρ_(max)无显著性差异(P>0.05)。大黄素甲醚及其代谢产物在大鼠体内平均驻留时间基本为10 h,并在16 h内消除。随给药剂量增加,代谢产物大黄素-8-O-β-D-葡萄糖苷,芦荟大黄素及大黄素血浆暴露量上升,出现轻度蓄积。结论大黄素甲醚给药后,原型及其代谢物在体内消除缓慢,因此应严格控制给药剂量和给药间隔,防止体内成分蓄积发生不良反应。

OBJECTIVE To establish a UPLC-QTOF-MS method for the determination of physcion and its metabolites in plasma,and to study the toxicokinetic(TK)behavior of its prototype and metabolites in rats.METHODS The TK of the prototype and its metabolites from the first to the end of administration was determined in a repeated-dosed toxicity study,the kinetic parameters were calculated,and degree of exposure of the prototype and metabolites in the plasma of rats after oral administration of different doses of physcion were evaluated.RESULTS In this study,there was no dose-dependent relationship between the plasma exposure of the prototype and metabolites after the first and last administration and the administration dose.The level of physcion detected in the sample from rats administered three doses all maintained at a high concentration without significant difference(P>0.05).Physcion and its metabolites were basically maintained for 10 hours in rats and eliminated within 16 hours.With the increase of administration doses,the plasma exposure of its metabolites emodin-8-O-β-D-glucoside,aloe-emodin and emodin were increased and accumulated slightly.CONCLUSION After administration of physcion,the prototype and its metabolites are slowly eliminated in the rats.To avoid its accumulation in the body and potential adverse reactions,the doses and administration intervals of physcion should be strictly controlled.