Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Japan.
Biol Pharm Bull. 2010;33(2):159-67. doi: 10.1248/bpb.33.159.
The circadian pacemaker of mammals resides in the paired suprachiasmatic nuclei (SCN) and influences a multitude of biological processes, including the sleep-wake rhythm. Clock genes are the genes that control the circadian rhythms in physiology and behavior. Twenty-four hour rhythm has been demonstrated for the function of physiology and the pathophysiology of diseases. The effectiveness and toxicity of many drugs vary depending on dosing time. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also the pharmacokinetics of medications. Thus, knowledge of the 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy. One approach to increasing the efficiency of pharmacotherapy is the administration of drugs at times at which they are most effective and/or best tolerated. Drugs for several diseases are still given without regard to the time of day. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. The mechanisms underlying chronopharmacological findings should be clarified from the viewpoint of clock genes. On the other hand, several drugs have an effect on the circadian clock. The knowledge of interactions between the circadian clock and a drug should be very useful in clinical practice. Therefore, the aim of this review is to provide an overview of the dosing time-dependent alterations in therapeutic outcome and safety of drugs. The mechanisms are introduced from the viewpoint of pharmaceutics.
哺乳动物的生物钟位于成对的视交叉上核（SCN）中，影响着许多生物过程，包括睡眠-觉醒节律。时钟基因是控制生理和疾病病理生理学中昼夜节律的基因。已经证明了 24 小时的生理功能和疾病的病理生理学节律。许多药物的有效性和毒性取决于给药时间。这种时间药理学现象不仅受到药物动力学的影响，还受到药物动力学的影响。因此，了解疾病风险的 24 小时节律以及药物药代动力学、作用和安全性的 24 小时节律依赖性的证据构成了药物治疗的基础。提高药物治疗效率的一种方法是在药物最有效和/或最耐受的时间给药。仍有一些疾病的药物没有考虑给药时间。识别选择给药时间的节律性标志物将导致chronopharmacotherapy 的进展和普及。应从时钟基因的角度阐明时间药理学发现的机制。另一方面，一些药物对生物钟有影响。了解生物钟与药物之间的相互作用在临床实践中应该非常有用。因此，本综述的目的是提供一个关于药物治疗效果和安全性的时间依赖性变化的概述。从药剂学的角度介绍了这些机制。
