The role of the circadian timing system on drug metabolism and detoxification: an update

ABSTRACT

Introduction

The 24-hour variations in drug absorption, distribution, metabolism, and elimination, collectively known as pharmacokinetics, are fundamentally influenced by rhythmic physiological processes regulated by the molecular clock. Recent advances have elucidated the intricacies of the circadian timing system and the molecular interplay between biological clocks, enzymes and transporters in preclinical level.

Area covered

Circadian rhythm of the drug metabolizing enzymes and carrier efflux functions possess a major role for drug metabolism and detoxification. The efflux and metabolism function of intestines and liver seems important. The investigations revealed that the ABC and SLC transporter families, along with cytochrome p-450 systems in the intestine, liver, and kidney, play a dominant role in the circadian detoxification of drugs. Additionally, the circadian control of efflux by the blood–brain barrier is also discussed.

Expert opinion

The influence of the circadian timing system on drug pharmacokinetics significantly impacts the efficacy, adverse effects, and toxicity profiles of various drugs. Moreover, the emergence of sex-related circadian changes in the metabolism and detoxification processes has underscored the importance of considering gender-specific differences in drug tolerability and pharmacology. A better understanding of coupling between central clock and circadian metabolism/transport contributes to the development of more rational drug utilization and the implementation of chronotherapy applications.

KEYWORDS:

• Chronopharmacology
• chronopharmacokinetics
• circadian rhythms
• metabolism
• transport
• detoxification

Article highlights

• Enzymes responsible for xenobiotic metabolism and influx/efflux transporters in the body play important role in drug metabolism and toxicity.

• Recent advances have elucidated that the circadian clock and clock-controlled transcription factors governs the rhythmic expression of enzymes as well as transporters.

• Improved knowledge of the circadian regulation of drug metabolism and transport opens new avenues for personalized medicine by offering insightful information about temporal dynamics of xenobiotic detoxification.

• Sexually dimorphic circadian changes in the metabolism and detoxification processes cause variation in the drug tolerability and responses between sex.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has been recruited by Research Square. Reviewers with declared or apparent competing interests are not utilized for these reviews. This reviewer was paid a small honorarium for completing the review within a specified timeframe. Honoraria for reviews such as this are paid regardless of the reviewer recommendation. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.