AstraZeneca, Mereside, Alderley Park, Cheshire, SK10 4TG, UK.
Drug Metab Dispos. 2011 Dec;39(12):2165-8. doi: 10.1124/dmd.111.040683. Epub 2011 Aug 31.
Accurately predicting in vivo metabolic clearance from in vitro liver microsomes or hepatocytes requires a good understanding of the factors contributing to the prediction. Although much work has concentrated on deriving scaling factors and optimizing the metabolic stability techniques for consistency and rigor, it is only relatively recently that the importance of binding to microsomes and hepatocytes has been appreciated. Ultrafiltration is often used to estimate binding to plasma proteins and microsomes, but the level of nonspecific binding (NSB) to the ultrafiltration apparatus has not been adequately described. We derive an equation to correct for NSB and demonstrate that this can significantly affect the estimate of binding to microsomes and improve the accuracy of scaling to in vivo clearance for a series of barbiturates.
准确地从体外肝微粒体或肝细胞预测体内代谢清除率需要很好地理解影响预测的因素。虽然有很多工作集中在推导缩放因子和优化代谢稳定性技术以保持一致性和严谨性，但直到最近才认识到与微粒体和肝细胞结合的重要性。超滤法常用于估计与血浆蛋白和微粒体的结合，但超滤装置的非特异性结合（NSB）水平尚未得到充分描述。我们推导出一个方程来纠正 NSB，并证明这可以显著影响对微粒体结合的估计，并提高一系列巴比妥类药物的体内清除率的缩放准确性。
