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
10.3867/j.issn.1000-3002.2025.04.006
- VernacularTitle: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
- Author:
Dawei FU
1
;
Yujin FU
;
Lailai YAN
;
Jie CHEN
;
Zhiyu LIU
;
Juanling FU
;
Biyun YAO
;
Weidong HAO
;
Peng ZHAO
Author Information
1. 北京大学公共卫生学院毒理学系,食品安全毒理学研究与评价北京市重点实验室,北京 100191
- Publication Type:Journal Article
- Keywords:
in vitro simulated one compartment extravascular administration model;
classic in vitro administration model;
toxicokinetics;
area under the curve;
lanthanum nitrate;
cell death
- From:
Chinese Journal of Pharmacology and Toxicology
2025;39(4):285-295,中插1-中插2
- CountryChina
- Language:Chinese
-
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.
