Circadian regulation of transporter expression and implications for drug disposition

ABSTRACT

Introduction: Solute Carrier (SLC) and ATP-binding cassette (ABC) transporters expressed in the intestine, liver, and kidney determine the absorption, distribution, and excretion of drugs. In addition, most molecular and cellular processes show circadian rhythmicity controlled by circadian clocks that leads to diurnal variations in the pharmacokinetics and pharmacodynamics of many drugs and affects their therapeutic efficacy and toxicity.

Area covered: This review provides an overview of the current knowledge on the circadian rhythmicity of drug transporters and the molecular mechanisms of their circadian control. Evidence for coupling drug transporters to circadian oscillators and the plausible candidates conveying circadian clock signals to target drug transporters, particularly transcription factors operating as the output of clock genes, is discussed.

Expert opinion: The circadian machinery has been demonstrated to interact with the uptake and efflux of various drug transporters. The evidence supports the concept that diurnal changes that affect drug transporters may influence the pharmacokinetics of the drugs. However, more systematic studies are required to better define the timing of pharmacologically important drug transporter regulation and determine tissue- and sex-dependent differences. Finally, the transfer of knowledge based on the results and conclusions obtained primarily from animal models will require careful validation before it is applied to humans.

KEYWORDS:

• Drug transport
• drug elimination
• circadian rhythms
• solute carriers
• ATP-binding cassette transporters
• liver
• intestine
• kidney

Article highlights

• Membrane transporters play important role in drug absorption, excretion, and entry into target organs and cells.

• There is clear evidence that drug transporters undergo rhythmic expression, which correlates with circadian variations of drug disposition and toxicity.

• The molecular circadian clock regulates the expression of drug transporter-encoding genes directly or indirectly through the circadian expression of clock-controlled transcription factors.

• There are species- and tissue-specific differences in the circadian expression of drug transporters.

• The studies were predominantly done on laboratory rodents. It will be necessary to validate these results and conclusions before their transfer to human physiology and pharmacology.

This box summarizes the key points contained in the article.

Acknowledgments

The authors wish to thank Prof. P. Baldi and Dr. M. Samad from the Dept. of Computer Science and Institute for Genomics & Bioinformatics, Univ. of California, Irvine, for providing us with the circadian data of mouse drug transporter genes based on circadian database CircadiOmics.

Reviewer disclosures

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

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.

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Additional information

Funding

This work was funded in part by a grant from the Czech Science Foundation (18-02993S) awarded to J. Pácha.