Systems biology approaches to enzyme kinetics: analyzing network models of drug metabolism

Intracellular drug metabolism involves transport, bioactivation, conjugation, and other biochemical steps. The dynamics of these steps are each dependent on a number of other cellular factors that can ultimately lead to unexpected behavior. In this review, we discuss the confounding processes and coupled reactions within bioactivation networks that require a systems-level perspective in order to fully understand the time-varying behavior. When converting known in vitro characteristics of drug-enzyme interactions into descriptions of cellular systems, features such as substrate availability, cell-to-cell variability, and intracellular redox state deserve special focus. An example of doxorubicin bioactivation is used for discussing points of consideration when constructing and analyzing network models of drug metabolism.