Department of Environmental and Occupational Health, School of Public Health, IRSPUM, Université de Montréal, Montreal, Quebec, Canada; Consultant Patrick Poulin Inc., Quebec City, Quebec, Canada.
Department of Environmental and Occupational Health, School of Public Health, IRSPUM, Université de Montréal, Montreal, Quebec, Canada.
J Pharm Sci. 2017 Nov;106(11):3207-3214. doi: 10.1016/j.xphs.2017.07.004. Epub 2017 Aug 18.
The hepatic clearance (CL) of bisphenol A (BPA) in the isolated perfused rat liver (IPRL) model has been studied for the impact of albumin (ALB) binding and coadministration with naproxen (NAP) in a companion manuscript (Bounakta et al. Xenobiotica. 2017;3:1-13.). We reported that the extrapolations of hepatic CL of BPA, NAP, and the binary mixtures between 2 ALB concentrations did not follow the free drug hypothesis; however, potential ALB-facilitated hepatic uptake mechanism(s) were highly suspected. Therefore, the objective of the present study was to reanalyze the IPRL data to provide a deeper quantitative extrapolation of CL; however, the focus was made on the impact of ALB binding on the intrinsic clearance (CL) versus unbound CL instead of only the global hepatic CL to verify whether the concept of ALB-facilitated hepatic uptake still holds for these 2 additional parameters for binary mixtures. Firstly, the variations in CL that were observed between the IPRL model using no ALB and ALB in the perfusates were compared to the corresponding variations in the unbound fraction measured in the perfusates (fu) according to the free drug hypothesis, or to the variations in the fu values adjusted for potential ALB-facilitated uptake mechanism (i.e., fu). The parameter fu showed a greater predictability compared to fu (average fold error ∼ 1 vs. 5.2), suggesting that both the free and bound drug moieties should be available for hepatic uptake. Secondly, the supplemental data analysis showed a greater decrease in unbound K than in V resulting in increased uptake CL of the unbound drug (V/unbound K) with increased ALB concentration at a given substrate concentration, which is compatible with an ALB-facilitated hepatic uptake mechanism. Interestingly, the unbound CL increased by a factor that corresponds to the bound drug moiety also assumed available for hepatic uptake. These additional findings corroborate the recent literature. Overall, this study showed the importance of quantifying any differential of ALB concentration (in vitro vs. in vivo or hypoalbuminemia in vivo vs. hyperalbuminemia in vivo) in the IPRL-based, in vitro-to-in vivo or in vivo-to-in vivo extrapolation-based or physiologically based pharmacokinetics-based CL prediction of chemical-drug interactions between xenobiotics significantly bound to ALB.
在一篇相关的随附论文中，我们研究了在离体灌流大鼠肝脏（IPRL）模型中，双酚 A（BPA）的肝清除率（CL）受白蛋白（ALB）结合的影响，并与萘普生（NAP）共同给药（Bounakta 等人，《生药学》。2017;3:1-13.）。我们报告说，BPA、NAP 和 2 种 ALB 浓度之间的二元混合物的肝 CL 外推不符合游离药物假说；然而，高度怀疑存在潜在的 ALB 促进的肝摄取机制。因此，本研究的目的是重新分析 IPRL 数据，以更深入地对 CL 进行定量外推；然而，重点是 ALB 结合对内在清除率（CL）与未结合 CL 的影响，而不是仅对整体肝 CL 的影响，以验证对于这两种二元混合物的另外两个参数，ALB 促进肝摄取的概念是否仍然成立。首先，比较了无 ALB 和灌流液中存在 ALB 的 IPRL 模型之间观察到的 CL 变化与根据游离药物假说测量的灌流液中未结合分数（fu）的相应变化，或与潜在的 ALB 促进摄取机制（即 fu）调整的 fu 值的变化。与 fu（平均折叠误差约为 1 对 5.2）相比，参数 fu 具有更好的预测性，这表明肝摄取应同时考虑游离和结合药物部分。其次，补充数据分析显示，未结合 K 的降低大于 V，导致在给定底物浓度下，随着 ALB 浓度的增加，未结合药物的摄取 CL 增加（V/未结合 K），这与 ALB 促进的肝摄取机制一致。有趣的是，与假设也可用于肝摄取的结合药物部分相对应，未结合 CL 增加了一个因子。这些额外的发现与最近的文献一致。总的来说，这项研究表明，在基于 IPRL 的、基于体外-体内或体内低白蛋白血症与体内高白蛋白血症的体外-体内或基于生理的药代动力学 CL 预测中，量化任何 ALB 浓度差异（体外与体内或体内低白蛋白血症与体内高白蛋白血症）对于量化化学-药物相互作用非常重要，这些相互作用显著结合了 ALB。
