大黄素型单蒽酮大鼠体内毒代动力学研究  

Toxicokinetics study of monanthone in rats in vivo

作　　者：汪祺[1] 杨建波[1] 王莹[1] 李妍怡 张玉杰[2] 文海若 马双成[1] WANG Qi;YANG Jian-bo;WANG Ying;LI Yan-yi;ZHANG Yu-yie;WEN Hai-ruo;MA Shuang-cheng(National Institutes for Food and Drug Control,Beijing 100050,China;Beijing University of Chinese Medicine,Beijing 100029,China)

机构地区：[1]中国食品药品检定研究院,北京100050 [2]北京中医药大学,北京100029

出　　处：《药物分析杂志》2022年第10期1720-1728,共9页Chinese Journal of Pharmaceutical Analysis

基　　金：国家自然科学基金资助项目(81973476)。

摘　　要：目的:建立用于血浆中大黄素型单蒽酮及其代谢产物含量测定的UPLC-Q TOF-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,流动相为乙腈(A)-0.1%甲酸(B),梯度洗脱(0~7 min,95%A→50%A;7~10 min,50%A→20%A;10~11 min,20%A→0%A),流速:0.4 mL·min^(-1),柱温:40℃;负离子扫描模式,毛细管电压1.0 kV,锥孔电压30 V,扫描范围m/z 50~1000计算动力学参数毒代动力学参数T_(max)、C_(max)、AUC_(all)及MRT_(last),评价大鼠口服不同剂量的大黄素型单蒽酮后大鼠血浆中原型及代谢产物的暴露程度。结果:研究发现大黄素型单蒽酮给药后,原型成分在大鼠体内的C_(max)分别为0.56μg·mL^(-1)(高浓度给药)、0.54μg·mL^(-1)(中浓度给药)、0.51μg·mL^(-1)(低浓度给药),体内AUC_(all)分别为1.13 h·μg·mL^(-1)(高浓度给药)、1.11 h·μg·mL^(-1)(中浓度给药)、1.18 h·μg·mL^(-1)(低浓度给药),不同剂量组中原型成分大鼠体内血浆暴露量无明显差异(P>0.05)。给药后原型及代谢产物的血药浓度基本在6 h内达到T_(max),并在20 h内消除。主要代谢产物为蒽醌(大黄素,羟基大黄素,芦荟大黄素)和蒽醌糖苷(大黄素-8-O-β-D-葡萄糖苷,芦荟大黄素-8-O-β-D-葡萄糖苷),原型及大部分代谢产物普遍可在体内停留20 h。随给药剂量增加芦荟大黄素、羟基大黄素及大黄素等则出现了轻度蓄积现象。结论:大黄素型单蒽酮给药后,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-Q TOF-MS method for the determination of emodin-type monoanthrone and its metabolites in plasma,and to study the toxicokinetic(TK)behavior of its prototype and metabolitesin rats.Methods:The TK of the prototype and its metabolites from the first administration to the end of administration was determined in the repeated-dosed toxicity study.The mobile phase was acetonitrile(A)-0.1%formic acid(B),gradient elution(0-7 min,95%A→50%A;7-10 min,50%A→20%A;10-11 min,20%A→0%A)negative ion scanning mode.Current speed was 0.4 mL·min^(-1).Column temperature was 40℃.Capillary voltage 1.0 kV,taper hole voltage 30 V,scanning range m/z 50-1000 the kinetic parameters T_(max),C_(max),AUC_(all)and MRT_(last)were calculated.Degrees of exposure of the prototype and metabolites in the plasma of rats after oral administration of different doses of emodin-type monoanthrone were evaluated.Results:In this study,after the administration of emodin-type monoanthrone,the C_(max)of prototype components in rats were 0.56μg·mL^(-1)(high concentration administration),0.54μg·mL^(-1)(medium concentration administration)and 0.51μg·mL^(-1)(low concentration administration),AUC_(all)in vivo were 1.13 h·μg·mL^(-1)(high concentration administration),1.11 h·μg·mL^(-1)(medium concentration administration),1.18 h·μg·mL^(-1)(low concentration administration),there was no significant difference in the plasma exposure of the prototype in rats,and its main metabolites were anthraquinone(emodin,hydroxyemodin,aloe-emodin)and anthracene quinone glycosides(emodin-8-O-β-D-glucoside,aloe-emodin-8-O-β-D-glucoside),the prototype and most metabolites were generally stay in the body for 20 h.Aloe-emodin,hydroxy-emodin and emodin appeared mild accumulation along with the increased doses.Conclusion:After administration of emodin-type monoanthrone,the prototype and its metabolites are eliminated slowly in the body.Therefore,the administration dose and interval of emodin-type monoanthrone should be strictly controlled t

关 键 词：毒代动力学 大黄素型单蒽酮 代谢产物 何首乌 液质联用 安全性 体内 毒性评价 

分 类 号：R917[医药卫生—药物分析学]