Genentech Inc., South San Francisco, California 94080, USA.
J Pharm Sci. 2012 Oct;101(10):3936-45. doi: 10.1002/jps.23235. Epub 2012 Jul 5.
Binding of drugs to plasma proteins is commonly considered in pharmacokinetics as being in an instantaneous equilibrium. Although if the timescale of dissociation of drug-protein complex becomes comparable to the time that a drug molecule spends in blood while passing through the elimination organ, the kinetics of protein binding may influence the organ clearance. This appears possible for the compounds that have large dissociation energy from protein. Typically, the dissociation of drug-protein complex is fast. However, the longest experimentally observed average bound time of drug to human albumin was as much as 11 min, whereas the time that a drug molecule spends in blood while passing through the liver is around 19 s. The equations for the calculation of hepatic clearance (Cl(h)) with the account of protein binding kinetics are derived for the well-stirred and parallel-tube models. It turns out that for drugs with very low extraction ratio, the influence of protein binding kinetics on Cl(h) is negligible; however, for drugs with high extraction ratio, it may lead to substantially smaller values (possibly by an order of magnitude) of Cl(h) compared with that provided by the common calculations.
药物与血浆蛋白的结合通常在药代动力学中被认为处于瞬时平衡状态。尽管如果药物-蛋白复合物的解离时间与药物分子在通过消除器官时在血液中停留的时间相当，那么蛋白结合的动力学可能会影响器官清除率。对于那些与蛋白解离能较大的化合物，这种情况似乎是可能的。通常，药物-蛋白复合物的解离速度很快。然而，在人类白蛋白上观察到的药物结合的最长平均结合时间长达 11 分钟，而药物分子在通过肝脏时在血液中停留的时间约为 19 秒。考虑到蛋白结合动力学，推导了用于计算肝清除率（Cl(h)）的方程，适用于完全搅拌和平行管模型。结果表明，对于提取率非常低的药物，蛋白结合动力学对 Cl(h)的影响可以忽略不计；然而，对于提取率高的药物，与常见计算相比，Cl(h)的值可能会显著减小（可能减小一个数量级）。
