Tracy Timothy S
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Drugs R D. 2006;7(6):349-63. doi: 10.2165/00126839-200607060-00004.
The Michaelis-Menten model is commonly used to estimate a drug's potential in vivo hepatic clearance based on in vitro data obtained during drug discovery and development. This paradigm assumes that the drug obeys 'typical' enzyme kinetics and thus can be described by this model. However, it is increasingly being recognised that a number of drugs metabolised not only by the cytochrome P450 enzymes but also by other enzymes and transporters can exhibit atypical kinetic profiles, and thus are not accurately modeled with the Michaelis-Menten model. Application of an incorrect model can then lead to mis-estimation of in vitro intrinsic clearance and thus affect the prediction of in vivo clearance. This review discusses several types of atypical kinetic profiles that may be observed, including examples of homotropic cooperativity (i.e. sigmoidal kinetics, biphasic kinetics and substrate inhibition kinetics) as well as heterotropic cooperativity (i.e. activation). Application of the incorrect kinetic model may profoundly affect estimations of intrinsic clearance. For example, incorrectly applying the Michaelis-Menten model to a kinetic profile exhibiting substrate inhibition kinetics will result in an underestimation of Km (Michaelis-Menten constant) and V(max) (maximal velocity), whereas application of the Michaelis-Menten model to sigmoidal kinetic data typically results in an overestimation of Km and V(max) at the lower substrate concentrations that are typically therapeutically relevant. One must also be careful of potential artefactual causes of atypical kinetic profiles, such as enzyme activation by solvents, buffer dependent kinetic profiles, or altered kinetic parameter estimates due to nonspecific binding of the substrate to proteins. Despite a plethora of data on the effects of atypical kinetic profiles in vitro, only modest effects have been noted in vivo (with the exception of substrate dependent inhibition). Thus, the clinical relevance of these phenomena remains inconclusive.
米氏模型通常用于根据药物研发过程中获得的体外数据来估算药物在体内的肝脏清除率。该范式假定药物遵循“典型”的酶动力学，因此可以用该模型进行描述。然而，人们越来越认识到，许多不仅由细胞色素P450酶代谢，还由其他酶和转运蛋白代谢的药物可能表现出非典型的动力学特征，因此不能用米氏模型进行准确建模。应用错误的模型可能会导致体外内在清除率的错误估计，进而影响体内清除率的预测。本综述讨论了可能观察到的几种非典型动力学特征，包括同促协同作用（即S形动力学、双相动力学和底物抑制动力学）以及异促协同作用（即激活）的例子。应用错误的动力学模型可能会深刻影响内在清除率的估计。例如，将米氏模型错误地应用于表现出底物抑制动力学的动力学特征将导致米氏常数（Km）和最大速度（V(max)）的低估，而将米氏模型应用于S形动力学数据通常会导致在通常具有治疗相关性的较低底物浓度下对Km和V(max)的高估。人们还必须小心非典型动力学特征的潜在人为原因，例如溶剂对酶的激活、缓冲液依赖性动力学特征，或由于底物与蛋白质的非特异性结合而改变的动力学参数估计。尽管有大量关于体外非典型动力学特征影响的数据，但在体内仅观察到适度的影响（底物依赖性抑制除外）。因此，这些现象的临床相关性仍然没有定论。
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