Worley Rachel Rogers, Fisher Jeffrey
Agency for Toxic Substances and Disease Registry, Division of Community Health Investigations, 4770 Buford Highway, Atlanta, GA 30341, United States; Interdisciplinary Toxicology Program, University of Georgia, 341 Pharmacy South, Athens, GA 30602, United States.
Interdisciplinary Toxicology Program, University of Georgia, 341 Pharmacy South, Athens, GA 30602, United States; Food and Drug Administration, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, United States.
Toxicol Appl Pharmacol. 2015 Dec 15;289(3):428-41. doi: 10.1016/j.taap.2015.10.017. Epub 2015 Nov 6.
Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter-mediated renal elimination. We developed a PBPK model for PFOA in male and female rats to explore the role of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both male and female rats indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex-specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contribute to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance.
成年大鼠中，全氟辛酸（PFOA）经肾脏清除及其从血清中的清除呈现出明显的性别差异。文献表明，这在很大程度上是由于近端肾小管细胞顶端和基底外侧膜上有机阴离子转运体（OATs）的表达受激素调节，这些转运体促进了PFOA从滤液中排泄并重吸收进入血液。先前建立的大鼠PFOA暴露的生理药代动力学（PBPK）模型尚未针对转运体介导的肾脏清除进行具体参数化。我们建立了雄性和雌性大鼠PFOA的PBPK模型，以探讨Oat1、Oat3和Oatp1a1在PFOA性别特异性肾脏重吸收和排泄中的作用。这些转运体的动力学行为描述是从体外研究推断而来的，该模型用于模拟两性静脉内（IV）和口服暴露后的血清、肝脏和尿液随时间变化的数据。模型预测的雄性和雌性大鼠肝脏、血清和尿液中PFOA的浓度与实验数据吻合良好，表明体外推导的转运体介导的肾脏重吸收的生理学描述能够成功预测大鼠中PFOA的性别依赖性排泄。本研究支持以下假设：PFOA的性别特异性血清半衰期在很大程度上由肾脏中转运体的表达驱动，并有助于将PBPK建模发展为评估转运体在肾脏清除中作用的工具。
