大鼠静注苯妥英钠的毒代动力学研究

Toxicokinetics of Phenytoin after Intravenous Injection Administration to Rats

目的:探讨苯妥英钠(DPH-Na)在大鼠血液的毒代动力学规律及组织分布。方法:大鼠静注中毒剂量DPH-Na后采集血液及组织样品,HPLC法测定其血浆及组织中药物浓度,分别用隔室模型拟合和米曼氏方程计算毒代动力学参数,并比较各组织中药物浓度。结果:DPH-Na静注中毒剂量后,在大鼠体内符合二室模型过程,主要毒代动力学参数:C_(max)=(61.31±7.09)μg·ml^(-1),t_(1/2)α=(0.18±0.08)h,t_(1/2β)=(2.60±0.52)h,AUC=(147.22±29.16)(μg·ml^(-1))·h,CL=(0.15±0.02)L·h^(-1)。按米曼氏方程解析所得主要毒代动力学参数:Vm=(10.42±5.33)μg·ml^(-1)·h^(-1),Km=(66.65±13.71)μg·ml^(-1),其余毒代动力学参数与二室模型拟合结果无明显差异(P>0.05)。DPH-Na在各组织中的浓度顺序依次为:肺>肾>肝>心>脑。结论:DPH-Na在大鼠体内的毒代动力学与药物动力学规律有差异,其中毒后在体内消除减慢,血液及组织中可能大量蓄积。

Objective： To study the toxicokinetics and distribution in tissue after intravenous injection administration of phenytoin to rats. Method：Each rat was given a toxie dose of phenytoin, the plasma and tissue samples of rats were collected on time after dosed. HPLC was used to determine the concentrations of phenytoin in plasma and tissue. Toxicokineties parameters of phenytoin were analyzed by compartment model and Michaelis-Menten. Result： Phenytoin showed two compartment model in rats and the main parameters of toxicokinetics were as follows：Cmax=（61.31±7.09）ug·ml^-1,t1/2a：（0.18±0.08）h,t1/2 B：（2.60±0.52）h,AUC=（147.22±29.16）（ug·ml^-1）·h,CL=（0.15±0.02）L·h^-1. The result of toxicokinetic parameters analyzed by Michaelis-Menten were as follows：Vm=（10.42±5.33）ug·ml^-1·h^-1,Km=（66.65±13.71）ug·ml^-1, the others were similar to compartment model. The concentration levels of phenytoin in tissues was lung 〉 kidney 〉 liver 〉 hear 〉 brain. Condusion： The toxieokineties course of phenytoin has disparation difference from pharmacokinetics in rats. The results suggested the possibility about the slow elimination from blood and accumulation in tissues of phenytoin after toxic dose administration to rats.