Circadian rhythm in pharmacokinetics and its relevance to chronotherapy.

Dosing time accounts for a large variability in efficacy and/or toxicity for many drugs. Therefore, chronotherapy has been shown to effectively improve drug efficacy and to reduce drug toxicity. Circadian changes in pharmacokinetics and pharmacodynamics (drug target) are two essential sources of time-varying drug effects. Pharmacokinetics determines the drug and metabolite concentrations (exposure) in target tissues/organs, thereby impacting drug efficacy and toxicity. Pharmacokinetic processes are generally divided into drug absorption, distribution, metabolism and excretion (so-called "ADME"). Recent years of studies have revealed circadian (~24 h) rhythms in ADME processes, and clarified the underlying mechanisms related to circadian clock regulation. Furthermore, there is accumulating evidence that circadian pharmacokinetics can be translated to chronotoxicity and chronoefficacy. In this article, we review circadian rhythms in pharmacokinetic behaviors along with the underlying mechanisms. We also discuss the correlations of circadian pharmacokinetics with chronotoxicity and chronoefficacy.