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Drug lipophilicity and microsomal protein concentration as determinants in the prediction of the fraction unbound in microsomal incubations

机译：药物亲脂性和微粒体蛋白浓度作为预测微粒体孵育中未结合部分的决定因素

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摘要

Two predictive tools have been proposed by Austin et al. (Drug Metab Dispos 30:1497-1503, 2002) and Hallifax and Houston (Drug Metab Dispos 34:724-726, 2006) to estimate the fraction unbound in the incubation (fuinc). The current study was undertaken to elucidate the relative utility of these prediction tools over a range of drug lipophilicity and microsomal protein concentration. The fuinc data set (n = 127) comprised 35 drugs determined experimentally in this study and 92 collated from Austin and Hallifax data. The observed fuinc values at three microsomal concentrations were compared with the estimates obtained using the Austin and Hallifax equations. In addition, the impact of variability in the logP on the fu inc predictions was assessed. The current analysis highlights the importance of accurate estimation of lipophilicity for the prediction of the fuinc, regardless of the prediction equation used. Both equations represent useful tools for estimation of fuinc for low lipophilicity drugs (logP/D = 0-3), especially at low microsomal protein concentration. However, the accuracy of fuinc predictions of highly lipophilic drugs was poor for both equations, implying that fuinc should be experimentally confirmed for drugs with logP/ D ≥ 3, unless the microsomal protein concentration is as low as 0.1 mg/ml, in which case a cutoff of logP/D ≥ 5 can be applied. A significant difference in the predictions by the two proposed tools was observed in the area of intermediate lipophilicity (logP/D = 2.5-5), where the Hallifax equation provided more accurate fuinc predictions on average, irrespective of the microsomal protein concentration investigated. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.
机译：Austin等人提出了两种预测工具。 （Drug Metab Dispos 30：1497-1503，2002）和Hallifax and Houston（Drug Metab Dispos 34：724-726，2006）来评估孵化中未结合的部分（fuinc）。进行当前的研究以阐明这些预测工具在药物亲脂性和微粒体蛋白浓度范围内的相对实用性。 fuinc数据集（n = 127）包括35项在本研究中实验确定的药物，以及92项从Austin和Hallifax数据整理的数据。将在三个微粒体浓度下观察到的岩藻糖值与使用Austin和Hallifax方程获得的估计值进行了比较。此外，评估了logP的可变性对fu inc预测的影响。当前的分析突显了精确估计亲脂性对于预测岩藻土的重要性，而与所使用的预测方程式无关。这两个方程式代表了用于评估低亲脂性药物（logP / D = 0-3）的岩藻多糖的有用工具，尤其是在低微粒体蛋白浓度下。但是，对于两个方程，对高度亲脂性药物进行fuinc预测的准确性均较差，这意味着对于logP / D≥3的药物，应通过实验确认fuinc，除非微粒体蛋白浓度低至0.1 mg / ml，在这种情况下可以采用logP / D≥5的临界值。在中等亲脂性方面（logP / D = 2.5-5），观察到了这两种拟议工具的预测存在显着差异，其中Hallifax方程平均提供了更准确的fuinc预测，而与所研究的微粒体蛋白浓度无关。版权所有©2008，美国药理与实验治疗学会。

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