Understanding circadian dynamics: current progress and future directions for chronobiology in drug discovery

ABSTRACT

Introduction

Most mammalian physiology is orchestrated by the circadian clock, including drug transport and metabolism. As a result, efficacy and toxicity of many drugs are influenced by the timing of their administration, which has led to the establishment of the field of chronopharmacology.

Areas covered

In this review, the authors provide an overview of the current knowledge about the time-of-day dependent aspects of drug metabolism and the importance of chronopharmacological strategies for drug development. They also discuss the factors influencing rhythmic drug pharmacokinetic including sex, metabolic diseases, feeding rhythms, and microbiota, that are often overlooked in the context of chronopharmacology. This article summarizes the involved molecular mechanisms and functions and explains why these parameters should be considered in the process of drug discovery.

Expert opinion

Although chronomodulated treatments have shown promising results, particularly for cancer, the practice is still underdeveloped due to the associated high cost and time investments. However, implementing this strategy at the preclinical stage could offer a new opportunity to translate preclinical discoveries into successful clinical treatments.

KEYWORDS:

• Circadian clock
• feeding rhythms
• chronopharmacology
• drug development
• liver
• xenobiotic metabolism
• microbiota
• obesity
• sex

Article highlights

• The concept of chronopharmacology is based on the fact that the time of administration affects drug efficacy and toxicity.

• The molecular mechanisms underlying chronopharmacology are linked to the circadian clock.

• The circadian clock and clock-controlled transcription factors drive the rhythmic expression of detoxification enzymes, which results in rhythmic drug detoxification.

• The circadian clock-regulated global physiology also influences drug metabolism and elimination of the metabolized compounds.

• Rhythmic drug metabolism varies with sex, metabolic diseases, and aging, as they impact circadian physiology.

• Recent evidence suggests that the fasting-feeding cycle and its effect on the rhythmic microbiome may also contribute to rhythmic drug metabolism.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

F Gachon receives support from the Institute for Molecular Bioscience, The University of Queensland, and from the National Health and Medical Research Council (Synergy grant # 2019260). BD Weger receives support from the National Health and Medical Research Council (Investigator grant # 2016334) and the Alzheimer’s Association Research Fellowship (AARF) (fellowship # AARF-22-917584).