University of Manitoba.
J Pharm Pharm Sci. 2014;17(1):34-91.
Hysteresis loops are phenomena that sometimes are encountered in the analysis of pharmacokinetic and pharmacodynamic relationships spanning from pre-clinical to clinical studies. When hysteresis occurs it provides insight into the complexity of drug action and disposition that can be encountered. Hysteresis loops suggest that the relationship between drug concentration and the effect being measured is not a simple direct relationship, but may have an inherent time delay and disequilibrium, which may be the result of metabolites, the consequence of changes in pharmacodynamics or the use of a non-specific assay or may involve an indirect relationship. Counter-clockwise hysteresis has been generally defined as the process in which effect can increase with time for a given drug concentration, while in the case of clockwise hysteresis the measured effect decreases with time for a given drug concentration. Hysteresis loops can occur as a consequence of a number of different pharmacokinetic and pharmacodynamic mechanisms including tolerance, distributional delay, feedback regulation, input and output rate changes, agonistic or antagonistic active metabolites, uptake into active site, slow receptor kinetics, delayed or modified activity, time-dependent protein binding and the use of racemic drugs among other factors. In this review, each of these various causes of hysteresis loops are discussed, with incorporation of relevant examples of drugs demonstrating these relationships for illustrative purposes. Furthermore, the effect that pharmaceutical formulation has on the occurrence and potential change in direction of the hysteresis loop, and the major pharmacokinetic / pharmacodynamic modeling approaches utilized to collapse and model hysteresis are detailed.
滞后环是在分析从临床前研究到临床研究的药代动力学和药效学关系时有时会遇到的现象。滞后环的出现提供了对药物作用和处置复杂性的深入了解，这种复杂性可能会遇到。滞后环表明，药物浓度与所测量的效应之间的关系不是简单的直接关系，而是可能具有内在的时间延迟和不平衡，这可能是代谢物的结果，药效学变化的结果，或者使用非特异性测定方法的结果，也可能涉及间接关系。逆时针滞后环通常被定义为在给定药物浓度下，效应随时间增加的过程，而在顺时针滞后环的情况下，给定药物浓度下的测量效应随时间减少。滞后环可能是由于许多不同的药代动力学和药效学机制引起的，包括耐受性、分布延迟、反馈调节、输入和输出速率变化、激动剂或拮抗剂活性代谢物、进入活性部位的摄取、受体动力学缓慢、延迟或改变活性、时间依赖性蛋白结合以及使用外消旋药物等因素。在这篇综述中，讨论了这些滞后环的各种原因，并结合了药物的相关实例来说明这些关系。此外，还详细介绍了药物制剂对滞后环发生和潜在方向变化的影响，以及用于压缩和模拟滞后环的主要药代动力学/药效学建模方法。
