Thakore K N, Gargas M L, Andersen M E, Mehendale H M
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
Toxicol Appl Pharmacol. 1991 Jul;109(3):514-28. doi: 10.1016/0041-008x(91)90014-6.
Pharmacokinetic modeling has been very useful in examining the complex relationships between exposure concentration and target tissue dose. This study utilizes a physiologically based pharmacokinetic (PB-PK) modeling approach for assessing the metabolism of BrCCl3 and to investigate its relationship with hepatotoxicity and lethality. Male Sprague-Dawley rats maintained for 15 days on normal diet (control), or on diets containing either chlordecone (CD, 10 ppm), phenobarbital (PB, 225 ppm) or mirex (M, 10 ppm), were used in gas uptake studies to determine the kinetic constants of BrCCl3 metabolism. Four initial concentrations of BrCCl3 at approximately 30, 200, 700, and 3000 ppm were used for each group. The uptake data were analyzed by computer simulation using a PB-PK model containing relevant tissue solubilities and physiological parameters as well as an equation describing the behavior of BrCCl3 in the closed chamber atmosphere. Liver injury was assessed by serum enzyme elevations (alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase) and histopathological examination, at 24 hr after the exposure to BrCCl3. Another group of similarly pretreated rats was exposed to BrCCl3 and observed over a 14-day period for mortality. Dietary exposures resulted in increased Vmaxc value for BrCCl3 metabolism as compared to control (3.55 +/- 0.14 mg/hr/kg) for PB (8.52 +/- 0.28 mg/hr/kg) and M (5.06 +/- 0.19 mg/hr/kg) but not for CD (3.92 +/- 0.19 mg/hr/kg). Kfc, the first-order rate constant for BrCCl3 metabolism, was decreased after PB (12.9 +/- 0.5 hr-1/kg) and increased after M (17.6 +/- 0.5 hr-1/kg), but unchanged after CD (15.5 +/- 0.6 hr-1/kg) exposure as compared to control (15.0 +/- 0.3 hr-1/kg). The total amount of BrCCl3 metabolism at any initial concentration employed remained unchanged in all the pretreated groups as compared to control. However, the amount of BrCCl3 metabolized through saturable pathway only, at higher initial concentrations, was increased in the PB and M pretreated groups, but not in the CD pretreated group. It is concluded that the rates of metabolism of BrCCl3 were unchanged after CD pretreatment as compared to control, while PB and M pretreatment alter both the saturable and first-order rates. Serum enzymes were significantly increased in all the groups after exposure to BrCCl3 at 200 and 700 ppm concentrations. The increase was more pronounced in PB and M pretreated groups as compared to control and CD pretreated groups. Similarly, histopathological examination of liver showed alterations in the lobular architecture, the extent of alterations being dependent on the dose of BrCCl3 and the pretreatment.(ABSTRACT TRUNCATED AT 400 WORDS)
药代动力学建模在研究暴露浓度与靶组织剂量之间的复杂关系方面非常有用。本研究采用基于生理学的药代动力学（PB-PK）建模方法来评估三氯溴甲烷的代谢，并研究其与肝毒性和致死率的关系。将雄性Sprague-Dawley大鼠分别以正常饮食（对照）、含开蓬（CD，10 ppm）、苯巴比妥（PB，225 ppm）或灭蚁灵（M，10 ppm）的饮食饲养15天，用于气体摄取研究以确定三氯溴甲烷代谢的动力学常数。每组使用约30、200、700和3000 ppm的四个初始三氯溴甲烷浓度。摄取数据通过计算机模拟进行分析，使用包含相关组织溶解度和生理参数的PB-PK模型以及描述三氯溴甲烷在封闭腔室气氛中行为的方程。在暴露于三氯溴甲烷24小时后，通过血清酶升高（丙氨酸转氨酶、天冬氨酸转氨酶和山梨醇脱氢酶）和组织病理学检查评估肝损伤。另一组经过类似预处理的大鼠暴露于三氯溴甲烷，并在14天内观察死亡率。与对照（3.55±0.14 mg/hr/kg）相比，饮食暴露导致PB（8.52±0.28 mg/hr/kg）和M（5.06±0.19 mg/hr/kg）组三氯溴甲烷代谢的Vmaxc值增加，但CD（3.92±0.19 mg/hr/kg）组未增加。三氯溴甲烷代谢的一级速率常数Kfc在PB处理后降低（12.9±0.5 hr-1/kg），在M处理后增加（17.6±0.5 hr-1/kg），但与对照（15.0±0.3 hr-1/kg）相比，CD处理后不变（15.5±0.6 hr-1/kg）。与对照相比，所有预处理组在任何使用的初始浓度下三氯溴甲烷代谢的总量均保持不变。然而，在较高初始浓度下，仅通过可饱和途径代谢的三氯溴甲烷量在PB和M预处理组中增加，而在CD预处理组中未增加。结论是，与对照相比，CD预处理后三氯溴甲烷的代谢速率不变，而PB和M预处理改变了可饱和和一级速率。在暴露于200和700 ppm浓度的三氯溴甲烷后，所有组的血清酶均显著增加。与对照和CD预处理组相比，PB和M预处理组的增加更为明显。同样，肝脏的组织病理学检查显示小叶结构改变，改变程度取决于三氯溴甲烷的剂量和预处理情况。（摘要截断于400字）
