敌草快在大鼠体内毒代动力学与组织分布研究

Toxicokinetic and tissue distribution after a single oral dose of diquat in Wistar rats

目的观察敌草快(diquat,DQ)在大鼠体内的毒代动力学及组织分布特点。方法取42只Wistar雄性大鼠,通过一次性灌胃染毒给予大鼠DQ 115.5 mg/kg(每100 mg体质量给予DQ溶液体积1 mL),其中24只大鼠用于毒代动力学研究,采用随机数字表法分成4组,每组每只在4个时间点采血,分别在给药前、给药后5 min、10 min、25 min、40 min、1 h、2.5 h、5 h、8 h、10 h、11 h、12 h、13 h、16 h、24 h、34 h于眼眶内取血1 mL;18只Wistar大鼠用于组织分布研究,采用随机数字表法分为3组,分别于吸收相(25 min)、平衡相(1 h)和消除相(1 d)三个时间点处死大鼠留取组织标本,采用超高效液相色谱-质谱联用仪对血浆及组织中DQ浓度进行测定。采用DAS 3.2.8软件对数据进行分析,绘制毒物浓度-时间曲线,计算其毒代动力学参数,并观察DQ在大鼠体内组织分布特点。结果毒代动力学研究发现,DQ达到血浆峰浓度的时间(time to maximum plasma concentration,Tmax)为(0.9±0.3)h,血浆峰浓度(maximum plasma concentration,Cmax)为(5287.5±2189.5)ng/mL。DQ在大鼠血液中的消除半衰期(half-life,t1/2)为(19.3±4.3)h,平均滞留时间(mean residence time,MRT)为(4.9±0.7)h,表观分布容积(apparent volume of distribution,Vz/F)为(242.0±15.7)L/kg,曲线下面积(area under the curve,AUC0-∞)为(13024.5±3305.7)mg/(h·L)。组织分布研究发现,DQ在大鼠体内分布广,几乎分布到各个器官,其中主要分布于小肠、胃和肾脏,而骨骼肌、脾脏和脑组织次之,心脏、肺脏、肝脏中仅有少量分布,且DQ在肺组织中无蓄积现象。结论DQ在体内吸收较快,给药后约1 h血浆浓度达峰值;DQ在体内分布广,几乎分布到各个器官,其中主要分布于小肠、胃和肾脏,而骨骼肌、脾脏和脑组织次之,心脏、肺脏、肝脏中仅有少量分布,且DQ在肺组织中无蓄积现象。

Objective To evaluate the toxicokinetic and tissue distribution of diquat(DQ)in the Wistar rats.Methods Forty-two fasted male Wistar rats were administered 115.5 mg/kg of DQ(1 mL/100 g body weight)by single-dose of intragastric administration.For toxicokinetic experiments,twenty-four fasted male Wistar rats were randomized into four groups.Blood samples were collected from rats at 4 different timepoints in each group.Blood samples(1.0 mL)were collected into heparinized Eppendorf tubes from the retrobulbar venous plexus of rats at 16 time points of pre-dose and after dose of 5 min,10 min,25 min,40 min,1,2.5,5,8,10,11,12,13,16,24 and 34 h.For tissue distribution experiments,eighteen fasted male Wistar rats were randomized into three groups,the rats were euthanized at the absorption phase(25 min),the equilibrium phase(1 h)and the elimination phase(1 d).Serial blood and tissue samples were taken respectively and analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS).The concentration versus time curve was constructed.Toxicokinetic parameters were calculated using the Drug and Statistics 3.2.8 software program,and tissue distribution characteristics of DQ in rats were observed.Results The mean time to reach the maximum concentration(Tmax)was 0.9±0.3 h.The maximum plasma concentration(Cmax)was(5287.5±2189.5)ng/mL.The average half-life(t1/2)and mean residence time(MRT)were(19.3±4.3)h and(4.9±0.7)h.The apparent volume of distribution(Vz/F)was(242±15.7)L/kg.The area under the concentration-time curve(AUC0-∞)was(13024.5±3305.7)mg/(h·L).DQ was absorbed rapidly from the gastrointestinal tract,and the peak concentration time of blood appeared at about 1h after dosing.DQ was widely distributed throughout the body,mainly in the small intestine,stomach and kidneys,followed by skeletal muscle,spleen and brain,only a small amount in heart,lungs and livers,and there was no accumulation of DQ in lungs.Conclusions DQ is absorbed rapidly from the gastrointestinal tract,and the peak concentration time of blood appeared is at about 1 h after dosing.DQ is widely distributed throughout the body,mainly in the small intestine,stomach and kidneys,followed by skeletal muscle,spleen and brain,only a small amount in heart,lungs and livers,and there is no accumulation of DQ in lungs.