Timing in drug absorption and disposition: The past, present, and future of chronopharmacokinetics.

The importance of drug dosing time in pharmacokinetics, pharmacodynamics, and toxicity is receiving increasing attention from the scientific community. In spite of mounting evidence that circadian oscillations affect drug absorption, distribution, metabolism, and excretion (ADME), there remain many unanswered questions in this field and, occasionally, conflicting experimental results. Such data arise not only from translational difficulties caused by interspecies differences but also from variability in study design and a lack of understanding of how the circadian clock affects physiological factors that strongly influence ADME, namely, the expression and activity of drug transporters. Hence, the main goal of this review is to provide an updated analysis of the role of the circadian rhythm in drug absorption, distribution across blood-tissue barriers, metabolism in hepatic and extra-hepatic tissues, and hepatobiliary and renal excretion. It is expected that the research suggestions proposed here will contribute to a tissue-targeted and time-targeted pharmacotherapy.