中国药理学与毒理学杂志2025，Vol.39Issue(4)：285-295,中插1-中插2,13.DOI:10.3867/j.issn.1000-3002.2025.04.006
体外模拟单室血管外给药染毒模型的构建及其与经典体外染毒模型在硝酸镧诱导HepG2细胞死亡中的比较
Construction of an in vitro simulated one compartment extravascular administration model and comparisons with a classic in vitro administration model in lanthanum nitrate induced HepG2 cell death
摘要
Abstract
OBJECTIVE To establish an in vitro simulated one compartment extravascular adminis-tration model with lanthanum nitrate as the test substance,and explore the differences between this model and the classic in vitro administration model in lanthanum nitrate induced HepG2 cell death.METHODS An in vitro administration device was designed based on compartment model theories which consisted of four functional chambers:the liquid storage chamber,mixing chamber,toxicant exposure chamber,and waste liquid receiving chamber.The four chambers were connected by peristaltic pump hoses.The peristaltic pumps were employed to ensure unidirectional and constant speed trans-mission of liquid between these chambers.According to the preset toxicokinetic parameters such as T1/2a and T1/2,an in vitro simulated one compartment extravascular administration model of lanthanum nitrate was constructed using the device.The content of lanthanum nitrate in the toxicant exposure chamber at different time points was measured using inductively coupled plasma mass spectrometry.The concentration-time curves of lanthanum nitrate were analyzed using PKsolver and GraphPad Prism 8.0 software.The constructed in vitro simulated one compartment extravascular administration model was evaluated by comparing the measured and theoretical values of toxicokinetic parameters.HepG2 cells were treated with lanthanum nitrate in the in vitro simulated one compartment extravascular administration model and classic in vitro administration model,respectively,and cell death was measured using the Hoechst 33342/propidium iodide staining method.RESULTS Within the Cmax range of 3.91-1 000.00 μmol·L-1,the measured concentration-time curves of lanthanum nitrate in the toxicant expo-sure chamber almost conformed with the corresponding calculated theoretical curves(the correlation coefficients were all>0.998 0).The measured values of toxicokinetic parameters,including Ke,T1/2,Ka,T1/2a,Tmax,Cmax,CL and AUC0-∞,were close to the corresponding theoretical values.The fitting coeffi-cients(R2)of the concentration-time curves for each experimental group were all>0.990 0,which was consistent with one compartment model for extravascular administration.In the simulated one compart-ment extravascular administration model,no significant death of HepG2 cells was observed in any lanthanum nitrate dose group.In the classic in vitro administration model,the cell death rate of the 0.500 mmol·L-1 lanthanum nitrate group was higher than that of the solvent control group,but no significant cell death was observed in the 0.119 mmol·L-1 group or 0.243 mmol·L-1 group.When Cmax or Cadministration was 0.500 mmol·L-1,classic in vitro administration induced a higher cell death rate than simulated one compart-ment extravascular administration.However,there was no statistically significant difference in lanthanum nitrate induced HepG2 cell death between the two administration models when the AUC was equal.CONCLUSION The device designed in this study can be used to in vitro simulate one compartment extravascular administration,making in vitro toxicity testing more similar to in vivo scenarios,and providing data for optimizing administration methods of in vitro toxicity testing.There are differences in lanthanum nitrate induced HepG2 cell death between simulated one compartment extravascular administration and classic in vitro administration,indicating that different in vitro exposure modes can affect toxicity.关键词
体外模拟单室血管外给药染毒模型/经典体外染毒模型/毒动学/曲线下面积/硝酸镧/细胞死亡Key words
in vitro simulated one compartment extravascular administration model/classic in vitro administration model/toxicokinetics/area under the curve/lanthanum nitrate/cell death分类
医药卫生引用本文复制引用
付大维,付于津,闫赖赖,陈洁,刘芷毓,付娟玲,姚碧云,郝卫东,赵鹏..体外模拟单室血管外给药染毒模型的构建及其与经典体外染毒模型在硝酸镧诱导HepG2细胞死亡中的比较[J].中国药理学与毒理学杂志,2025,39(4):285-295,中插1-中插2,13.基金项目
国家自然科学基金(81370079) （81370079）
国家自然科学基金(81001253) （81001253）
北京市自然科学基金(7132122) National Natural Science Foundation of China(81370079) （7132122）
National Natural Science Foundation of China(81001253) （81001253）
and Beijing Natural Science Foundation(7132122) （7132122）
