Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
Laboratory Animal Research Department, Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, Japan.
Chem Res Toxicol. 2020 Dec 21;33(12):3048-3053. doi: 10.1021/acs.chemrestox.0c00387. Epub 2020 Dec 6.
Bromobenzene is an industrial solvent that elicits toxicity predominantly in the liver. In this study, the hepatic concentrations of bromobenzene and its related compounds 1,2-dibromobenzene and 1,4-dibromobenzene in humanized-liver mice were predicted after single oral administrations by simplified physiologically based pharmacokinetic (PBPK) models that had been set up on experimental plasma concentrations after single oral doses of 100 mg/kg to rats and 100-250 mg/kg to control mice and humanized-liver mice. The output values by simplified PBPK models were consistent with measured blood substrate concentrations in rats, control mice, and humanized-liver mice with suitable input parameter values derived from in silico prediction and the literature or estimated by fitting the measured plasma substrate concentrations. The predicted time-dependent hepatic concentrations after virtual administrations in humanized-liver mice were partly confirmed with single measured hepatic concentrations of bromobenzene and 1,4-dibromobenzene 2 h after oral doses of 150-250 mg/kg to humanized-liver mice. Moreover, leaked human albumin mRNA, a marker of the extent of human hepatic injuries, in humanized-liver mouse plasma was detected after oral administration of bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene. These results suggest that dosimetry approaches for determining tissue and/or blood exposures of hepatic toxicants bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene in humanized-liver mice were useful after virtual oral doses using simplified PBPK models. Using simplified PBPK models and plasma data from humanized-liver mice has potential to predict and evaluate the hepatic toxicity of bromobenzenes and related compounds in humanized-liver mice and in humans.
溴苯是一种工业溶剂，主要在肝脏中引起毒性。在这项研究中，通过简化的基于生理学的药代动力学（PBPK）模型预测了人源化肝脏小鼠单次口服 100mg/kg 至大鼠和 100-250mg/kg 至对照小鼠和人源化肝脏小鼠后肝脏中溴苯及其相关化合物 1,2-二溴苯和 1,4-二溴苯的肝浓度。简化 PBPK 模型的输出值与大鼠、对照小鼠和人源化肝脏小鼠的实测血基质浓度一致，合适的输入参数值源自计算机预测和文献中的值或通过拟合实测血浆基质浓度来估计。在虚拟给药后，人源化肝脏小鼠中预测的时间依赖性肝浓度与溴苯和 1,4-二溴苯在人源化肝脏小鼠口服 150-250mg/kg 后 2 小时的单次实测肝浓度部分吻合。此外，在口服给予溴苯、1,2-二溴苯和 1,4-二溴苯后，人源化肝脏小鼠血浆中漏出的人白蛋白 mRNA（肝损伤程度的标志物）被检测到。这些结果表明，在人源化肝脏小鼠中，用于确定肝毒物溴苯、1,2-二溴苯和 1,4-二溴苯的组织和/或血液暴露的剂量测定方法在使用简化 PBPK 模型进行虚拟口服剂量后是有用的。使用简化的 PBPK 模型和人源化肝脏小鼠的血浆数据有可能预测和评估溴苯和相关化合物在人源化肝脏小鼠和人类中的肝毒性。
