Zhao Ping
Sonus Pharmaceuticals, Bothell, WA 98021, USA.
Expert Opin Drug Metab Toxicol. 2008 Feb;4(2):151-64. doi: 10.1517/17425255.4.2.151.
Time-dependent inactivation (TDI) of P450 is an important mechanism of drug interactions. The quantitative in vitro - in vivo correlation of TDI using systems such as human liver microsomes requires a comprehensive understanding of in vitro kinetics, pharmacokinetics, inhibition mechanisms, and homeostasis of the enzyme being inactivated.
To evaluate the use of hepatocytes in predicting TDI.
The theoretical basis of in vitro - in vivo correlation of TDI and the progress in using microsomes and hepatocytes to predict TDI in vivo are reviewed.
RESULTS/CONCLUSION: Factors that may impact prediction accuracy, such as nonspecific binding, metabolism of inactivator, active transport, and sequential inhibitory metabolites, can be assessed by performing 'in vitro-in vitro' correlation between microsomes and hepatocytes. Together with microsomal data and the aid of computer modeling and simulation, hepatocytes provide a powerful tool to optimize the integrated approaches aimed at quantitatively predicting TDI in vivo.
细胞色素P450的时间依赖性失活（TDI）是药物相互作用的重要机制。使用人肝微粒体等系统进行TDI的体外-体内定量相关性研究需要全面了解体外动力学、药代动力学、抑制机制以及被失活酶的稳态。
评估肝细胞在预测TDI中的应用。
综述TDI体外-体内相关性的理论基础以及使用微粒体和肝细胞预测体内TDI的进展。
结果/结论：通过在微粒体和肝细胞之间进行“体外-体外”相关性研究，可以评估可能影响预测准确性的因素，如非特异性结合、失活剂代谢、主动转运和顺序抑制性代谢产物。结合微粒体数据并借助计算机建模和模拟，肝细胞为优化旨在定量预测体内TDI的综合方法提供了有力工具。
