Impact of gut permeability on estimation of oral bioavailability for chemicals in commerce and the environment.

IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Gregory S Honda, Elaina M Kenyon, Sarah Davidson-Fritz, Roger Dinallo, Hisham El Masri, Evgenia Korol-Bexell, Li Li, Derek Angus, Robert G Pearce, Risa R Sayre, Christopher Strock, Russell S Thomas, Barbara A Wetmore, John F Wambaugh
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Abstract

Performance of pharmacokinetic models developed using in vitro-to-in vivo extrapolation (IVIVE) methods may be improved by refining assumptions regarding fraction absorbed (Fabs) through the intestine, a component of oral bioavailability (Fbio). Although in vivo measures of Fabs are often unavailable for non-pharmaceuticals, in vitro measures of apparent permeability (Papp) using the Caco-2 cell line have been highly correlated with Fabs. We measured bidirectional Papp for over 400 non-pharmaceutical chemicals using the Caco-2 assay. A random forest quantitative structure-property relationship (QSPR) model was developed using these and peer-reviewed pharmaceutical data. Both Caco-2 data (R²=0.37) and the QSPR model (R²=0.29) were better at predicting human bioavailability compared to in vivo rat data (R²=0.23). After incorporation into a high throughput toxicokinetics (HTTK) framework for IVIVE, the Caco-2 data were used to estimate in vivo administered equivalent dose (AED) for bioactivity assessed in vitro, The HTTK-predicted plasma steady state concentrations (Css) for IVIVE were revised, with modest changes predicted for poorly absorbed chemicals. Experimental data were evaluated for sources of measurement uncertainty, which were then accounted for using the Monte Carlo method. Revised AEDs were subsequently compared with exposure estimates to evaluate effects on bioactivity:exposure ratios, a surrogate for risk. Only minor changes in the margin between chemical exposure and predicted bioactive doses were observed due to the preponderance of highly absorbed chemicals.

肠道渗透性对商业和环境中化学品口服生物利用度估算的影响。
使用体外到体内外推法(IVIVE)建立的药代动力学模型的性能,可以通过改进有关通过肠道吸收的部分(Fabs)的假设来提高,这是口服生物利用度(Fbio)的一个组成部分。虽然非药物通常无法在体内测量吸收率,但利用 Caco-2 细胞系在体外测量表观渗透性(Papp)与吸收率高度相关。我们利用 Caco-2 试验测定了 400 多种非药物化学物质的双向 Papp。利用这些数据和同行评议的制药数据,我们建立了一个随机森林定量结构-性质关系(QSPR)模型。与大鼠体内数据(R²=0.23)相比,Caco-2 数据(R²=0.37)和 QSPR 模型(R²=0.29)都能更好地预测人体生物利用度。在将 IVIVE 纳入高通量毒代动力学(HTTK)框架后,Caco-2 数据被用于估算体外生物活性评估的体内给药当量剂量(AED)。对实验数据进行了测量不确定性来源评估,然后使用蒙特卡罗方法对其进行了说明。修订后的 AEDs 随后与暴露估计值进行了比较,以评估对生物活性:暴露比率(一种风险替代物)的影响。由于高度吸收的化学品占绝大多数,因此只观察到化学品暴露量与预测生物活性剂量之间的差值发生了微小变化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Altex-Alternatives To Animal Experimentation
Altex-Alternatives To Animal Experimentation MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
7.70
自引率
8.90%
发文量
89
审稿时长
2 months
期刊介绍: ALTEX publishes original articles, short communications, reviews, as well as news and comments and meeting reports. Manuscripts submitted to ALTEX are evaluated by two expert reviewers. The evaluation takes into account the scientific merit of a manuscript and its contribution to animal welfare and the 3R principle.
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