Yang Xiaoxia, Doerge Daniel R, Teeguarden Justin G, Fisher Jeffrey W
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
Toxicol Appl Pharmacol. 2015 Dec 15;289(3):442-56. doi: 10.1016/j.taap.2015.10.016. Epub 2015 Oct 29.
A previously developed physiologically based pharmacokinetic (PBPK) model for bisphenol A (BPA) in adult rhesus monkeys was modified to characterize the pharmacokinetics of BPA and its phase II conjugates in adult humans following oral ingestion. Coupled with in vitro studies on BPA metabolism in the liver and the small intestine, the PBPK model was parameterized using oral pharmacokinetic data with deuterated-BPA (d6-BPA) delivered in cookies to adult humans after overnight fasting. The availability of the serum concentration time course of unconjugated d6-BPA offered direct empirical evidence for the calibration of BPA model parameters. The recalibrated PBPK adult human model for BPA was then evaluated against published human pharmacokinetic studies with BPA. A hypothesis of decreased oral uptake was needed to account for the reduced peak levels observed in adult humans, where d6-BPA was delivered in soup and food was provided prior to BPA ingestion, suggesting the potential impact of dosing vehicles and/or fasting on BPA disposition. With the incorporation of Monte Carlo analysis, the recalibrated adult human model was used to address the inter-individual variability in the internal dose metrics of BPA for the U.S. general population. Model-predicted peak BPA serum levels were in the range of pM, with 95% of human variability falling within an order of magnitude. This recalibrated PBPK model for BPA in adult humans provides a scientific basis for assessing human exposure to BPA that can serve to minimize uncertainties incurred during extrapolations across doses and species.
先前开发的成年恒河猴双酚A（BPA）基于生理学的药代动力学（PBPK）模型经过修改，以表征成年人类口服摄入后BPA及其II相共轭物的药代动力学。结合肝脏和小肠中BPA代谢的体外研究，使用过夜禁食后在饼干中递送的氘代BPA（d6-BPA）的口服药代动力学数据对PBPK模型进行参数化。未结合的d6-BPA血清浓度时间过程的可用性为BPA模型参数的校准提供了直接的经验证据。然后，针对已发表的BPA人体药代动力学研究，对重新校准的成人BPA PBPK模型进行了评估。需要一个口服摄取减少的假设来解释在成年人类中观察到的峰值水平降低，其中d6-BPA在汤中递送，并且在摄入BPA之前提供食物，这表明给药载体和/或禁食对BPA处置的潜在影响。通过纳入蒙特卡罗分析，重新校准的成人模型用于解决美国普通人群BPA内部剂量指标的个体间变异性。模型预测的BPA血清峰值水平在pM范围内，95%的人类变异性在一个数量级内。这种重新校准的成人BPA PBPK模型为评估人类接触BPA提供了科学依据，有助于最大限度地减少跨剂量和物种外推过程中产生的不确定性。
