Chronopharmaceutics: pharmaceutics focused on biological rhythm

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.