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首页> 外文期刊>Journal of Pharmacological and Toxicological Methods >Direct determination of the ratio of unbound fraction in plasma to unbound fraction in microsomal system (fu p/fu mic) for refined prediction of phase I mediated metabolic hepatic clearance.
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Direct determination of the ratio of unbound fraction in plasma to unbound fraction in microsomal system (fu p/fu mic) for refined prediction of phase I mediated metabolic hepatic clearance.

机译：直接测定血浆中未结合部分与微粒体系统中未结合部分的比率（fu p / fu mic），以精确预测I期介导的代谢性肝清除率。

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At the drug discovery stage, in vivo metabolic hepatic clearance (CL(hep)) is commonly predicted using in vitro parent compound disappearance data generated in liver microsomes or hepatocytes. Correction for the unbound fraction of a compound in the in vitro system and in plasma/serum is known to be critical for the accuracy of metabolic clearance predictions. Discrete generation of these required experimental parameters can be laborious. Herein, we describe a straightforward and direct approach to obtain the ratio of unbound fraction in plasma (fu(p)) to unbound fraction in the microsomal system (fu(mic)) of a small molecule compound using equilibrium dialysis. Experimental conditions were optimized with respect to incubation time, temperature, and plate shaking speed. Results obtained from this system were validated for a set of test compounds by comparison to individually measured fu(p) and fu(mic) data using ultracentrifugation. The correlation for fu(p)/fu(mic) between the two methods for a set of 23 data points was very good with R(2) of 0.94, slope of 1.05 and an intercept of 0.007. The impact of microsomal binding on predicted CL(hep) was illustrated for a tightly bound compound using a series of incubations with increasing concentration of monkey liver microsomal protein. Alteration of this experimental parameter profoundly affected calculated CL(hep) using the well-stirred model. Significant differences were observed in the prediction when the model was corrected for fu(p) only; in contrast, the model corrected for plasma protein and microsomal protein binding predicted clearance values independent of the microsomal protein concentration.
机译：在药物发现阶段，通常使用肝微粒体或肝细胞中产生的体外母体化合物消失数据来预测体内代谢性肝清除率（CL（hep））。已知体外系统和血浆/血清中化合物未结合部分的校正对于代谢清除率预测的准确性至关重要。这些必需的实验参数的离散生成可能很费力。在本文中，我们描述了一种直接且直接的方法，该方法使用平衡透析获得小分子化合物的微粒体系统的血浆未结合部分（fu（p））与微粒体系统中未结合部分的比率（fu（mic））。关于孵育时间，温度和平板摇动速度，对实验条件进行了优化。通过使用超速离心与单独测得的fu（p）和fu（mic）数据进行比较，验证了从该系统获得的结果，适用于一组测试化合物。一组23个数据点的两种方法之间fu（p）/ fu（mic）的相关性非常好，R（2）为0.94，斜率为1.05，截距为0.007。使用一系列随着猴肝微粒体蛋白浓度增加的温育，对紧密结合的化合物说明了微粒体结合对预测的CL（hep）的影响。使用良好搅拌的模型，更改此实验参数会严重影响计算的CL（hep）。仅针对fu（p）校正模型时，在预测中观察到了显着差异。相反，校正血浆蛋白和微粒体蛋白结合的模型预测的清除率值独立于微粒体蛋白浓度。

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