Faculty of Pharmaceutical Sciences, Kyushu University.
Biol Pharm Bull. 2021;44(11):1577-1584. doi: 10.1248/bpb.b21-00476.
Daily rhythmic variations in biological functions affect the efficacy and/or toxicity of drugs: a large number of drugs cannot be expected to exhibit the same potency at different administration times. The "circadian clock" is an endogenous timing system that broadly regulates metabolism, physiology and behavior. In mammals, this clock governs the oscillatory expression of the majority of genes with a period length of approximately 24 h. Genetic studies have revealed that molecular components of the circadian clock regulate the expression of genes responsible for the sensitivity to drugs and their disposition. The circadian control of pharmacodynamics and pharmacokinetics enables 'chrono-pharmaceutical' applications, namely drug administration at appropriate times of day to optimize the therapeutic index (efficacy vs. toxicity). On the other hand, a variety of pathological conditions also exhibit marked day-night changes in symptom intensity. Currently, novel therapeutic approaches are facilitated by the development of chemical compound targeted to key proteins that cause circadian exacerbation of disease events. This review presents an overview of the current understanding of the role of the circadian biological clock in regulating drug efficacy and disease conditions, and also describes the importance of identifying the difference in the circadian machinery between diurnal and nocturnal animals to select the most appropriate times of day to administer drugs in humans.
生物功能的日常节律变化会影响药物的疗效和/或毒性：不能期望大量药物在不同给药时间表现出相同的效力。“生物钟”是一种内源性计时系统，广泛调节代谢、生理和行为。在哺乳动物中，这个时钟控制着大多数基因的振荡表达，其周期长度约为 24 小时。遗传研究表明，生物钟的分子组成部分调节着对药物敏感性和药物处置负责的基因的表达。药效学和药代动力学的昼夜节律控制使得“chrono-pharmaceutical”应用成为可能，即根据需要在一天中的适当时间给药，以优化治疗指数（疗效与毒性）。另一方面，许多病理状况在症状强度方面也表现出明显的昼夜变化。目前，通过开发针对导致疾病事件昼夜节律恶化的关键蛋白的化学化合物，为新的治疗方法提供了便利。本文综述了生物钟在调节药物疗效和疾病状况中的作用的最新认识，还描述了确定昼行性和夜行性动物之间昼夜节律机制差异的重要性，以便选择在人类中给药的最适时间。
