Hepatotoxicological potential of P-toluic acid in humanised-liver mice investigated using simplified physiologically based pharmacokinetic models
Hepatotoxicological potential of P-toluic acid in humanised-liver mice investigated using simplified physiologically based pharmacokinetic models
复制标题
使用简化的基于生理学的药代动力学模型研究对甲基苯甲酸在人源化肝小鼠中的肝毒理学潜力
DOI：
10.1080/00498254.2021.1908643
复制
发表时间：
2021
期刊：
影响因子：
1.8
通讯作者：
Yamazaki Hiroshi
中科院分区：
文献类型：
--
作者：
Miura Tomonori;Kamiya Yusuke;Uehara Shotaro;Murayama Norie;Shimizu Makiko;Suemizu Hiroshi;Yamazaki Hiroshi
对甲苯甲酸是有机溶剂二甲苯的代谢产物，在大鼠中报告的无明显作用水平较高（诺埃尔，1000 mg/kg），可能是由于甘氨酸直接结合至甲基马尿酸。在这项研究中，对甲苯甲酸及其甘氨酸结合物在小鼠和人源化肝小鼠口服给药后的血浆水平进行了评估，虽然从小鼠血浆浓度可以明显看出对甲苯甲酸迅速转化为甘氨酸结合物，但对甲苯甲酸在人源化肝小鼠中的生物转化较慢。生理药代动力学（PBPK）模型的输入参数采用拟合程序确定，以建立PBPK生成的血药浓度曲线。PBPK模型的对甲基苯甲酸在人源化肝小鼠中的肝浓度高于在血浆中观察到的浓度。PBPK模型的肝脏和血浆中对甲基苯甲酸浓度也表明在人体中消除缓慢，这些结果表明，据报道在大鼠中观察到的对甲基苯甲酸的快速结合可能导致外推至人源化肝脏小鼠或人类时高估可结合化学品的NOEL。
p-Toluic acid, a metabolite of organic solvent xylene, has a high reported no‐observed‐effect level (NOEL, 1000 mg/kg) in rats, possibly because of direct glycine conjugation to methylhippuric acid. In this study, plasma levels ofp-toluic acid and its glycine conjugate in mice and humanised-liver mice were evaluated after oral administrations.Although rapid conversion ofp-toluic acid to its glycine conjugate was evident from mouse plasma concentrations, the biotransformation ofp-toluic acid was slower in humanised-liver mice. The input parameters for physiologically based pharmacokinetic (PBPK) models were determined using fitting procedures to create PBPK-generated plasma concentration curves.The PBPK-modelled hepatic concentrations ofp-toluic acid in humanised-liver mice were higher than those observed in plasma. PBPK-modelled hepatic and plasma concentrations ofp-toluic acid also indicated slow elimination in humans.These results suggest that rapid conjugations ofp-toluic acid reportedly observed in rats could result in overestimation of NOELs for conjugatable chemicals when extrapolated to humanised-liver mice or humans.