Trends in Molecular Medicine
ReviewDosing-Time Makes the Poison: Circadian Regulation and Pharmacotherapy
Section snippets
The Role of the Circadian Timing System in Xenobiotics Detoxification
Recent scientific evidence highlights the critical role of circadian rhythms (see Glossary) for the metabolism and effects of xenobiotics, including drugs as well as environmental toxicants (Figure 1). Since 2011, there has been increased awareness on the regulation of circadian rhythms in pharmacology or toxicology. Conceptual and methodological progress has enabled the tracking of circadian patterns in cells, tissues, experimental animals, and human beings 1, 2, 3, 4, 5, 6. These new insights
Dosing-Time Dependencies of Xenobiotic Effects
Drug development aims to define a recommended dose for a potential new compound based on the majority of individual subjects, irrespective of timing, sex, age, lifestyle, or comorbidities. However, unanticipated or overwhelming adverse effects represent severe limitations, resulting in both drug attrition 33, 34 and postmarketing withdrawal of several otherwise effective medications 35, 36. Moreover, some countries, such as the UK, are now terminating the reimbursement of several medications
A New Way Forward: In Vitro–In Silico Circadian Modulation of Xenobiotics Effects
The tight coordination of metabolic pathways across the day shows strong interindividual variance, but can also be altered, in particular whenever pathological processes or treatments disrupt the CTS. Therefore, there is a need for a systems approach to chronopharmacology to systematically map the key clock-controlled metabolic processes and test the consequences of their alterations on chronopharmacology. Expectedly, such systems chronopharmacology will help make a priori predictions of the
Usefulness of Circadian ‘Omics’
The in vivo and in vitro drug metabolism circadian investigation approaches might indeed benefit from ‘omics’ technologies. Multiple pharmacology and toxicology studies have shown that circadian clocks regulate key molecular pathways of drug metabolism in animal models. For studies of liver drug metabolism, various recent transcriptomic, proteomic, and metabolomic circadian datasets are now available from mice 103, 104, 105, 106, 107. This has been extremely useful for systems biology
Effects of Drugs on the CTS
The CTS modulates drug pharmacology and toxicology through a multitude of processes. There is growing evidence of the effects of drugs on the CTS, as shown by the circadian disruption of rest–activity, body temperature, or clock gene expression patterns. In mice and human patients receiving chemotherapeutic drugs, severe alterations of physiological rhythms have been observed 6, 121, 122. Broadly, these drugs can be grouped into (i) those exhibiting unintentional side effects or unspecific
Effects of Xenobiotics on the CTS
Chemotherapeutic drugs in particular have been described to have resetting and dampening effects on circadian oscillations. These agents can also unintentionally modify the CTS by either disrupting CTS coordination or by altering circadian amplitude or phase. As such, the CTS can represent a toxicity target to be shielded through proper circadian drug timing. Indeed, certain indicators of CTS coordination such as rest/activity and core body temperature can be severely disrupted by anticancer
Chronodrugs – Clocks as Targets
The hidden resetting of clocks by drugs presents a problem in terms of proper timing for repeated daily dosing. Interestingly, the dosing-time-dependent toxicity persists or is even amplified during the chronic dosing of anticancer agents such as taxane-derived docetaxel, the alkylators carboplatin and oxaliplatin, or the cyclin-dependent kinase inhibitor seliciclib [79]. This finding is in line with the dosing-time dependency of drug-induced circadian disruption. However, targeting specific
Concluding Remarks
Circadian clocks modulate many molecular pathways of human physiology and pathophysiology. An increasing amount of evidence indicates that there is a biologically and medically relevant impact of time-of-day on pharmacotherapy. Recent chronopharmacology studies involving cancer, rheumatology, hematology, neurological/psychiatric disorders, and cardiovascular medicine have been undertaken (Table 1, Table 2). Indeed, circadian clocks modulate many processes that define drug properties and
Acknowledgments
F.L. is supported by Cancer Research UK (CRUK) funding. We thank Monique Lévi for help with the preparation of this manuscript.
Glossary
- Chronotype
- or the diurnal preference of an individual is based at least partially genetically determined, but is plastic to a certain degree. Previously, variation of chronotype with age, sex, and behaviour (e.g., shift work, habits) has been described.
- Circadian amplitude and phase
- are two parameters that characterise the extent of variation and the timing of a rhythm with an approximately 24-h period.
- Circadian rhythm
- a temperature compensated biological rhythm with a period of approximately 1 day
References (173)
- et al.
Measuring circadian clock function in human cells
Methods Enzymol.
(2015) Daily eating patterns and their impact on health and disease
Trends Endocrinol. Metab.
(2016)- et al.
Circadian clock control of liver metabolic functions
Gastroenterology
(2016) Circadian disruption accelerates liver carcinogenesis in mice
Mutat. Res.
(2009)- et al.
Health consequences of circadian disruption in humans and animal models
Prog. Mol. Biol. Transl. Sci.
(2013) Carcinogenicity of shift-work, painting, and fire-fighting
Lancet Oncol.
(2007)- et al.
Chemical chronobiology: toward drugs manipulating time
FEBS Lett.
(2015) Chronotherapy and the molecular clock: clinical implications in oncology
Adv. Drug Deliv. Rev.
(2010)Blood-borne circadian signal stimulates daily oscillations in actin dynamics and SRF activity
Cell
(2013)The human circadian clock entrains to sun time
Curr. Biol.
(2007)
Scheduled wheel access during daytime: a method for studying conflicting zeitgebers
Physiol. Behav.
Lack of food anticipation in Per2 mutant mice
Curr. Biol.
Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet
Cell Metab.
Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges
Cell Metab.
A Smartphone App reveals erratic diurnal eating patterns in humans that can be modulated for health benefits
Cell Metab.
Circadian factor BMAL1 in histaminergic neurons regulates sleep architecture
Curr. Biol.
Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells
Cell
The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification
Cell Metab.
Pharmacologic modulation of reduced glutathione circadian rhythms with buthionine sulfoximine: relationship with cisplatin toxicity in mice
Toxicol. Appl. Pharmacol.
The ABCs of membrane transporters in health and disease (SLC series): introduction
Mol. Aspects Med.
Intestinal expression of mouse Abcg2/breast cancer resistance protein (BCRP) gene is under control of circadian clock-activating transcription factor-4 pathway
J. Biol. Chem.
Diurnal rhythmicity in the transcription of jejunal drug transporters
J. Pharmacol. Sci.
Identification of negative transcriptional factor E4BP4-binding site in the mouse circadian-regulated gene Mdr2
Neurosci. Res.
Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle
Proc. Natl. Acad. Sci. U.S.A.
Human cellular differences in cAMP–CREB signaling correlate with light-dependent melatonin suppression and bipolar disorder
Eur. J. Neurosci.
Real-time recording of circadian liver gene expression in freely moving mice reveals the phase-setting behavior of hepatocyte clocks
Genes Dev.
Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells
Mol. Syst. Biol.
Thoracic surface temperature rhythms as circadian biomarkers for cancer chronotherapy
Chronobiol. Int.
Coupling between the circadian clock and cell cycle oscillators: implication for healthy cells and malignant growth
Front. Neurol.
Chronopharmacology: new insights and therapeutic implications
Annu. Rev. Pharmacol. Toxicol.
Circadian rhythms: mechanisms and therapeutic implications
Annu. Rev. Pharmacol. Toxicol.
Cancer chronotherapeutics: experimental, theoretical, and clinical aspects
Handb. Exp. Pharmacol.
Acute effects of bright light exposure on cortisol levels
J. Biol. Rhythms
Rhythms and pharmacokinetics
Circadian clocks and drug delivery systems: impact and opportunities in chronotherapeutics
Exp. Opin. Drug Deliv.
Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M)
Diabetes Care
Efficacy and safety of morning versus evening dose of controlled-release simvastatin tablets in patients with hyperlipidemia: a randomized, double-blind, multicenter phase III trial
Clin. Ther.
Can levothyroxine be taken as evening dose? Comparative evaluation of morning versus evening dose of levothyroxine in treatment of hypothyroidism
J. Thyroid Res.
Time of administration important? Morning versus evening dosing of valsartan
J. Hypertens.
A circadian clock transcription model for the personalization of cancer chronotherapy
Cancer Res.
Serum factors in older individuals change cellular clock properties
Proc. Natl. Acad. Sci. U.S.A.
Circadian behavior is light-reprogrammed by plastic DNA methylation
Nat. Neurosci.
Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank
Nat. Commun.
GWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person
Nat. Commun.
Disturbed diurnal rhythm alters gene expression and exacerbates cardiovascular disease with rescue by resynchronization
Hypertension
Clock genes and metabolic disease
J. Appl. Physiol.
Metabolism and the circadian clock converge
Physiol. Rev.
The circadian timing system in clinical oncology
Ann. Med.
Can the pharmaceutical industry reduce attrition rates?
Nat. Rev. Drug Discov.
An analysis of the attrition of drug candidates from four major pharmaceutical companies
Nat. Rev. Drug Discov.
Cited by (176)
Circadian neurogenetics and its implications in neurophysiology, behavior, and chronomedicine
2024, Neuroscience and Biobehavioral ReviewsDevelopment, optimization and in-vivo pharmacokinetic evaluation of flubiprofen nanocrystal tablets for efficient chronotherapy against rheumatoid arthritis
2024, Journal of Drug Delivery Science and TechnologyTaking biological rhythms into account: From study design to results reporting
2024, Physiology and Behavior