Inhibition-based metabolic drug-drug interactions: predictions from in vitro data.
Inhibition-based metabolic drug-drug interactions: predictions from in vitro data.
复制标题
DOI：
10.1002/jps.10179
复制
发表时间：
2002-09
影响因子：
3.8
通讯作者：
C. Yao;R. Levy
中科院分区：
文献类型：
--
作者：
C. Yao;R. Levy
从体外系统预测体内代谢药物-药物相互作用的兴趣越来越大。高通量筛选方法旨在评估候选药物与药物相互作用的潜力，在工业上被广泛使用。然而，目前对于能够产生可靠的定量预测的方法还没有达成共识，因为许多问题仍然没有解决，例如体外抑制常数的估计和体内酶位点周围的抑制剂浓度的估计。本文总结了不同的方法来估计酶位点附近的抑制物浓度，并提出了由于孵育条件和体内外环境的差异而导致的与体外K(I)值估计有关的问题。讨论了一种通过计算体内抑制常数来比较体外和体内抑制力的新方法。描述了基于机理失活的体内药物相互作用预测的例子。还对允许进一步改进现有预测模型的未解决问题进行了评估。
There has been a growing interest in predicting in vivo metabolic drug-drug interactions from in vitro systems. High-throughput screening methods aimed at assessing the potential of drug candidates for drug interactions are widely used in industry. However, at present, there is no consensus on methodologies that would yield reliable quantitative predictions, because a number of issues remain unsolved, such as estimations of inhibition constants in vitro and inhibitor concentration around the enzyme site in vivo. In the present review, different approaches to estimation of inhibitor concentration around the enzyme site are summarized; also, the problems associated with estimation of in vitro K(i) values due to incubation conditions and environment differences between in vitro and in vivo are presented. A new approach based on comparisons of in vitro and in vivo inhibition potencies by calculation of in vivo inhibition constants is discussed. Examples of predictions of in vivo drug interactions based on mechanism-based inactivation are described. Unresolved issues that would allow further refinement of existing prediction models are also evaluated.