Circadian rhythms: influence on physiology, pharmacology, and therapeutic interventions

Abstract

Circadian rhythms are ubiquitous phenomena that recur daily in a self-sustaining, entrainable, and oscillatory manner, and orchestrate a wide range of molecular, physiological, and behavioral processes. Circadian clocks are comprised of a hierarchical network of central and peripheral clocks that generate, sustain, and synchronize the circadian rhythms. The functioning of the peripheral clock is regulated by signals from autonomic innervation (from the central clock), endocrine networks, feeding, and other external cues. The critical role played by circadian rhythms in maintaining both systemic and tissue-level homeostasis is well established, and disruption of the rhythm has direct consequence for human health, disorders, and diseases. Circadian oscillations in both pharmacokinetics and pharmacodynamic processes are known to affect efficacy and toxicity of several therapeutic agents. A variety of modeling approaches ranging from empirical to more complex systems modeling approaches have been applied to characterize circadian biology and its influence on drug actions, optimize time of dosing, and identify opportunities for pharmacological modulation of the clock mechanisms and their downstream effects. In this review, we summarize current understanding of circadian rhythms and its influence on physiology, pharmacology, and therapeutic interventions, and discuss the role of chronopharmacometrics in gaining new insights into circadian rhythms and its applications in chronopharmacology.

Keywords: Chronobiology; Chronotherapeutics; Circadian rhythms; Drug disposition; Molecular clock; Pharmacodynamics; Systems pharmacology.

Fig. 1

The molecular mechanism of the circadian clock in mammals—an autoregulatory transcriptional feedback loop involving core activators, core negative feedback repressors, accessory feedback loops, additional regulatory proteins, and tissue-specific clock-controlled output genes. Clock, Circadian Locomotor Output Cycles Kaput; Bmal, Brain-muscle Arnt like 1; Per, Period; Cry, Cryptochrome; ROR, retinoic acid related-orphan receptor; CK1, casein kinase 1; PP1, protein phosphatase 1; CCG, clock-controlled genes

Fig. 2

Integrative regulation of central and peripheral circadian clocks at the systemic level via (1) autonomic innervation of peripheral tissues, (2) endocrine signaling, and (3) environmental/behavioral signals. SCN suprachiasmatic nucleus, CRF corticotropin-releasing factor, GnRH gonadotropin-releasing hormone, FSH follicle stimulating hormone, LH luteinizing hormone, ACTH adrenocorticotropic hormone

Fig. 3

Diversity of circadian rhythms in human physiology. The peak time or acrophase of several biological processes in humans are shown relative to the sleep–wake cycle. Adapted from Smolensky and Peppas (2007) and Scherholz et al. (2019). TNF-α, tumor necrosis factor-α; IFN-γ, interferon- γ, IL-6, interleukin-6; TSH, thyroid stimulating hormone; ACTH, adrenocorticotropic hormone

Fig. 4

Schematic representing a systems pharmacology approach in integrating circadian biology, physiology and PK/PD. Conceptualization of relevant information use and integration of knowledge is shown using broken arrows. See Figs. 1 and 2 for full details contained within the boxes shown on the top-right (‘Circadian Biology’) and top-left (‘Physiology and Disease’)