中国药理学与毒理学杂志2024，Vol.38Issue(1)：39-45,7.DOI:10.3867/j.issn.1000-3002.2024.01.005
α-鹅膏蕈碱在大鼠体内的毒代动力学与组织分布特征
Toxicokinetics and tissue distribution of alpha-amanitin in rats
摘要
Abstract
OBJECTIVE To study the toxicokinetics and tissue distribution characteristics of alpha-amanitin in rats.METHODS The tail venous blood was collected from SD rats before and 5,10,20,30 and 45 min,1,1.5,2.5,4 and 8 h after intraperitoneal injection of alpha-amanitin(1.5 mg·kg-1),and the concentration of alpha-amanitin in blood was determined by liquid chromatography-mass spectrometry(LC-MS/MS).DAS 2.0 software was used to analyze and plot the drug-time curve with toxicokinetic parame-ters.Based on the toxicokinetics results,18 SD rats were randomly divided into three groups.The rats were sacrificed,and left ventricular arterial(LVA)blood and 9 types of tissue samples involving the heart,liver,spleen,lung,kidney,whole brain,small intestine,stomach wall and testis were collected 15 min,40 min and 2.5 h after dosing,and the concentrations of alpha-amanitin were measured by LC-MS/MS to obtain the tissue distribution results of alpha-amanitin in SD rats.RESULTS Toxicokinetics studies revealed that the peak blood concentration(Cmax)was(633±121)μg·L-1,the elimination half-life(T1/2)was(0.72±0.37)h,and the peak time(Tmax)was(0.52±0.16)h.The total clearance rate(CLz)was(1.62±0.26)L·h·kg-1,the area under the curve(AUC0-t)was(946±183)μg·h·L-1,and the mean reten-tion time(MRT0-t)was(1.18±0.17)h.The apparent volume of distribution(Vz)was(1.65±0.86)L·kg-1.The results of tissue distribution study showed that alpha-amanitin was widely distributed in SD rats with the highest concentration in the kidney,followed by the lung,small intestines,stomach wall,LVA blood and liver,but was low in the heart,spleen,testicles and other tissues,and very low in the brain.Alpha-amanitin was absorbed and eliminated quickly,peaked at 40 min in each tissue,and the concen-tration was minimized after 2.5 h.CONCLUSION The absorption and elimination of alpha-amanitin by intraperitoneal injection are rapid in SD rats,and the blood concentration reaches the peak about 31 min after administration,but can not be detected 4 h later.Alpha-amanitin is mainly distributed in the kidney,followed by the tissues and metabolic organs with rich blood flow,such as the lung,small intestines,stomach wall,LVA blood and liver.The content of alpha-amanitin is low in the heart,spleen,testicles and other tissues,and very low in the brain.It is speculated that it may have toxic targeting effect on the kidney and low blood-brain barrier permeability.关键词
α-鹅膏蕈碱/毒代动力学/组织分布/液相色谱-串联质谱法Key words
alpha-amanitin/toxicokinetics/tissue distribution/liquid chromatography-mass spec-trometry分类
医药卫生引用本文复制引用
卢玉梅,李树华,付旭宪,罗芳,朱恩槿,熊根,赵金阳,付廷昊,聂胜洁,王蕊..α-鹅膏蕈碱在大鼠体内的毒代动力学与组织分布特征[J].中国药理学与毒理学杂志,2024,38(1):39-45,7.基金项目
国家重点研发计划(2018YFC0807201-4) （2018YFC0807201-4）
昆明医科大学有毒药用植物活性成分发现与利用省创新团队(202005AE160004) National Key Research and Development Program(2018YFC0807201-4) （202005AE160004）
and Provincial Innovation Team for Discovery and Utilization of Active Ingredients of Toxic Medicinal Plants in Kunming Medical University(202005AE160004) （202005AE160004）
