Veng-Pedersen P, Widness J A, Wang J, Schmidt R L
University of Iowa, Iowa City 52242, USA.
J Pharmacokinet Biopharm. 1997 Oct;25(5):569-93. doi: 10.1023/a:1025765330455.
A drug tracer is most commonly applied to get information about the pharmacokinetics (PK) of a drug that is not confounded by an endogenously produced drug or an unknown drug input. An equally important use of tracers that has not been fully recognized is their use in the study of nonlinear PK behavior. In the present study a system analysis is applied to examine the interaction between drug molecules characteristic and intrinsic to any nonlinear process which enables the nonlinearity to be identified and modeled using a drug tracer. The proposed Tracer Interaction Methodology (TIM) forms a general developmental framework for novel methods for examining nonlinear phenomena. Such methods are potentially much more sensitive and accurate than previous methods not exploiting the tracer principle. The methodology proposed is demonstrated in a simulation study and with real data in a specific implementation aimed at determining the Michaelis-Menten (MM) parameters of nonlinear drug elimination while accounting for drug distribution effects. The simulation study establishes that the TIM-based, MM parameter evaluation produces substantially more accurate parameter estimates than a nontracer (NT) conventional method. In test simulations the accuracy of the TIM was in many cases an order of magnitude better than the NT method without evidence of bias. The TIM-based, MM parameter estimation methodology proposed is ideally suitable for dynamic, non-steady-state conditions. Thus, it offers greater applicability and avoids the many problems specific to steady state evaluations previously proposed. TIM is demonstrated in an evaluation of the nonlinear elimination behavior of erythropoietin, a process that likely takes place via receptor-based endocytosis. Due to its high sensitivity, accuracy, and intrinsic nonlinearity the TIM may be suitable for in-vivo studies of receptor binding of the many biotechnology produced peptide drugs and endogenous compounds displaying receptor-mediated elimination.
药物示踪剂最常用于获取有关药物药代动力学（PK）的信息，该信息不会因内源性产生的药物或未知的药物输入而混淆。示踪剂尚未得到充分认识的一个同样重要的用途是其在非线性PK行为研究中的应用。在本研究中，应用系统分析来检查药物分子特性与任何非线性过程内在的相互作用，从而能够使用药物示踪剂识别和建模非线性。所提出的示踪剂相互作用方法（TIM）为研究非线性现象的新方法形成了一个通用的发展框架。这类方法可能比以前未利用示踪剂原理的方法更加灵敏和准确。在一项模拟研究以及针对确定非线性药物消除的米氏（MM）参数同时考虑药物分布效应的具体实施中的实际数据中，展示了所提出的方法。模拟研究表明，基于TIM的MM参数评估比非示踪剂（NT）传统方法产生的参数估计要准确得多。在测试模拟中，TIM的准确性在许多情况下比NT方法高一个数量级，且无偏差迹象。所提出的基于TIM的MM参数估计方法非常适合动态、非稳态条件。因此，它具有更高的适用性，避免了先前提出的稳态评估所特有的许多问题。在对促红细胞生成素的非线性消除行为的评估中展示了TIM，促红细胞生成素的消除过程可能通过基于受体的内吞作用发生。由于其高灵敏度、准确性和内在非线性，TIM可能适用于对许多生物技术生产的肽类药物和显示受体介导消除的内源性化合物的受体结合进行体内研究。
