The impact of desorption kinetics and permeation kinetics on in vitro-based predictions of in vivo hepatic blood clearances is investigated in the present study. Most commonly, possible limitations due to slow desorption of chemicals from albumin or slow permeation of chemicals through cellular membranes are not considered when in vivo clearances are predicted from in vitro biotransformation rate constants. To evaluate whether the most commonly used extrapolation models might thus overlook important kinetic limitations, we compare predictions of in vivo clearance that explicitly consider desorption and permeation kinetics with predictions of in vivo clearance that neglect these aspects.

Our results show that strong limitations due to slow permeation kinetics are possible depending on the assumed permeability value. While permeability values estimated with a mechanistic approach are fast enough to avoid significant limitations, other experimentally derived permeability values lead to dramatically decreased in vivo clearance predictions. These latter values lead to unrealistically low in vivo biotransformation estimates. Furthermore, we also evaluated the implications of desorption kinetics using experimentally determined desorption rate constants. These evaluations show that slow desorption kinetics are unlikely to limit in vivo clearance.

在本研究中研究了解吸动力学和渗透动力学对基于体内肝脏血液清除率的体外预测的影响。最常见的是，当根据体外生物转化速率常数预测体内清除率时，不考虑由于白蛋白中的化学物质缓慢解吸或化学物质通过细胞膜缓慢渗透而引起的可能的局限性。为了评估是否最常用的外推模型，因而有可能忽略一些重要的动力学限制，我们比较的预测在体内清除明确考虑的预测解吸和吸收动力学体内 疏忽忽略了这些方面。

我们的结果表明，取决于假设的渗透率值，可能会由于渗透动力学慢而产生强大的局限性。虽然用机械方法估算的渗透率值足够快，可以避免明显的局限性，但其他实验得出的渗透率值却导致体内清除率预测值急剧下降。这些后面的值导致体内生物转化估计值低得不切实际。此外，我们还使用实验确定的解吸速率常数评估了解吸动力学的含义。这些评估表明缓慢的解吸动力学不太可能限制体内清除率。