Battelle Pacific Northwest Division, Richland, WA 99352, USA.
Toxicol Appl Pharmacol. 2011 Feb 1;250(3):229-44. doi: 10.1016/j.taap.2010.10.011. Epub 2010 Nov 11.
A previously developed PBPK model for ethylene glycol and glycolic acid was extended to include glyoxylic acid, oxalic acid, and the precipitation of calcium oxalate that is associated with kidney toxicity in rats and humans. The development and evaluation of the PBPK model was based upon previously published pharmacokinetic studies coupled with measured blood and tissue partition coefficients and rates of in vitro metabolism of glyoxylic acid to oxalic acid, glycine and other metabolites using primary hepatocytes isolated from male Wistar rats and humans. Precipitation of oxalic acid with calcium in the kidneys was assumed to occur only at concentrations exceeding the thermodynamic solubility product for calcium oxalate. This solubility product can be affected by local concentrations of calcium and other ions that are expressed in the model using an ion activity product estimated from toxicity studies such that calcium oxalate precipitation would be minimal at dietary exposures below the NOAEL for kidney toxicity in the sensitive male Wistar rat. The resulting integrated PBPK predicts that bolus oral or dietary exposures to ethylene glycol would result in typically 1.4-1.6-fold higher peak oxalate levels and 1.6-2-fold higher AUC's for calcium oxalate in kidneys of humans as compared with comparably exposed male Wistar rats over a dose range of 1-1000 mg/kg. The converse (male Wistar rats predicted to have greater oxalate levels in the kidneys than humans) was found for inhalation exposures although no accumulation of calcium oxalate is predicted to occur until exposures are well in excess of the theoretical saturated vapor concentration of 200mg/m(3). While the current model is capable of such cross-species, dose, and route-of-exposure comparisons, it also highlights several areas of potential research that will improve confidence in such predictions, especially at low doses relevant for most human exposures.
先前开发的用于乙二醇和甘醇酸的 PBPK 模型现已扩展，以包括乙醛酸、草酸和与大鼠和人类肾毒性相关的草酸钙沉淀。PBPK 模型的开发和评估基于先前发表的药代动力学研究，以及用雄性 Wistar 大鼠和人类分离的原代肝细胞测量的血液和组织分配系数和体外代谢乙醛酸为草酸、甘氨酸和其他代谢物的速率。假设仅在肾脏中钙与草酸的浓度超过草酸钙热力学溶解度产品时才会发生草酸钙沉淀。这种溶解度产品可受局部钙浓度和其他离子的影响，这些离子在模型中用从毒性研究中估计的离子活度乘积来表示，使得在低于敏感雄性 Wistar 大鼠肾毒性的无观察不良效应水平（NOAEL）的饮食暴露下，草酸钙沉淀最小。综合 PBPK 预测，口服或饮食摄入乙二醇会导致人与雄性 Wistar 大鼠相比，峰值草酸水平高出 1.4-1.6 倍，肾脏中草酸钙 AUC 高出 1.6-2 倍，剂量范围为 1-1000mg/kg。相反，对于吸入暴露，发现（预测雄性 Wistar 大鼠的肾脏中草酸水平高于人类），但预计直到暴露远远超过 200mg/m(3)的理论饱和蒸气浓度，才会发生草酸钙的积累。虽然当前模型能够进行这种跨物种、剂量和暴露途径的比较，但它也突出了几个潜在的研究领域，这将提高对这些预测的信心，特别是在与大多数人类暴露相关的低剂量下。
