Circadian clock-controlled drug metabolism and transport

Zhao, Min; Xing, Huijie; Chen, Min; Dong, Dong; Wu, Baojian

doi:10.1080/00498254.2019.1672120

Cited by 25 publications

(25 citation statements)

References 99 publications

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“…and RORE or RevRE) in the target gene promoter (Fig. 2) ( (Takahashi, 2017;Zhao et al, 2019a)). These cis-elements generate a difference in the phase (peak timing) of circadian gene expression (Minami et al, 2013).…”

Section: Regulation Of Drug-metabolizing Enzymes By Circadian Clock Genesmentioning

confidence: 99%

Circadian Clock–Controlled Drug Metabolism: Implications for Chronotherapeutics

Zhao

Chen

et al. 2020

Drug Metab Dispos

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Dependence of drug metabolism on dosing time has long been recognized. However, only recently are the underlying mechanisms for circadian drug metabolism being clarified. Diurnal rhythmicity in expression of drug-metabolizing enzymes is believed to be a key factor determining circadian metabolism. Supporting the notion that biological rhythms are generated and maintained by the circadian clock, a number of diurnal enzymes are under the control of the circadian clock. In general, circadian clock genes generate and regulate diurnal rhythmicity in drug-metabolizing enzymes via transcriptional actions on one or two of three cis-elements (i.e., E-box, D-box, and Rev-erb response element or RAR-related orphan receptor response element). Additionally, cycling or clockcontrolled nuclear receptors such as hepatocyte nuclear factor 4a and peroxisome proliferator-activated receptor g are contributors to diurnal enzyme expression. These newly discovered mechanisms for each of the rhythmic enzymes are reviewed in this article. We also discuss how the rhythms of enzymes are translated to circadian pharmacokinetics and drug chronotoxicity, which has direct implications for chronotherapeutics. Our discussion is also extended to two diurnal transporters (P-glycoprotein and multidrug resistance-associated protein 2) that have an important role in drug absorption. Although the experimental evidence is lacking in metabolism-based chronoefficacy, circadian genes (e.g., Reverba) as drug targets are shown to account for diurnal variability in drug efficacy. SIGNIFICANCE STATEMENTSignificant progress has been made in understanding the molecular mechanisms for generation of diurnal rhythmicity in drugmetabolizing enzymes. In this article, we review the newly discovered mechanisms for each of the rhythmic enzymes and discuss how the rhythms of enzymes are translated to circadian pharmacokinetics and drug chronotoxicity, which has direct implications for chronotherapeutics.

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Section: Regulation Of Drug-metabolizing Enzymes By Circadian Clock Genesmentioning

confidence: 99%

Circadian Clock–Controlled Drug Metabolism: Implications for Chronotherapeutics

Zhao

Chen

et al. 2020

Drug Metab Dispos

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“…This was followed by ultrasonication for about 30 min until a uniform dispersing solution was formed. The uniform dispersing solution was stored at 4°C prior to use ( Zhao et al, 2020b ).…”

Section: Methodsmentioning

confidence: 99%

“…Strychnine, brucine, triptolide and their metabolites were quantified using a UPLC-QTOF/MS system (Waters, Milford, MA, United States) consisting of a Waters ACQUITY UPLC and a Xevo G2 QTOF/MS as described in our previous publications ( Zhao et al, 2020b ; Gao et al, 2021 ). Chromatographic separation was performed on an ACE UltraCore SuperC18 column (Phenomenex, Torrance, CA, United States) with a flow rate of 0.3 ml/min.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics-Based Chronoefficacy of Semen Strychni and Tripterygium Glycoside Tablet Against Rheumatoid Arthritis

et al. 2021

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Rheumatoid arthritis is a systemic autoimmune disease characterized by synovial inflammation and bone destruction. Identifying drugs with time-varying efficacy and toxicity, and elucidating the mechanisms would help to improve treatment efficacy and reduce adverse effects. Here, we aimed to determine the chronoefficacy of semen strychni (SS) and tripterygium glycoside tablet (TGT) against rheumatoid arthritis in mice, and to investigate a potential role of circadian pharmacokinetics in generating chronoefficacy. SS extract and TGT suspension were prepared with ultrasonication. Effects of SS and TGT on collagen-induced arthritis (CIA) were evaluated by measuring TNF-α and IL-6 levels. SS dosed at ZT18 was more effective in protecting against CIA than drug dosed at ZT6 (i.e., lower levels of key inflammatory factors at ZT18 than at ZT6). This was accompanied by higher systemic exposure levels of strychnine and brucine (two main putative active ingredients of SS) in ZT18-treated than in ZT6-treated CIA mice. TGT dosing at ZT2 showed a better efficacy against CIA as compared to herb doing at ZT14. Consistently, ZT2 dosing generated a higher exposure of triptolide (a main putative active ingredient of TGT) as compared to ZT14 dosing in CIA mice. Moreover, strychnine, brucine, and triptolide significantly inhibited the proliferation of fibroblast-like synoviocytes, and reduced the production of TNF-α and IL-6 and the mRNAs of TNF-α, IL-6, COX-2, and iNOS, suggesting that they possessed an anti-arthritis activity. In conclusion, SS and TGT display chronoefficacy against rheumatoid arthritis in mice, that is attributed to circadian pharmacokinetics of main active ingredients. Our findings have implications for improving treatment outcomes of SS and TGT via timed delivery.

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“…Seasonality in PRR expression that show increased expression during the winter months (Dopico et al, 2015) alters the quality of vaccine responses and correlates with better protection against yellow fever virus (Querec et al, 2009). These simple measures of timing drug or vaccine administration can increase drug efficiency and reduce side effects (Ruben et al, 2019; Zhao et al, 2020).…”

Section: Perfect Timing: Approaches For Therapymentioning

confidence: 99%

The Circadian Clock and Viral Infections

2020

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The circadian clock controls several aspects of mammalian physiology and orchestrates the daily oscillations of biological processes and behavior. Our circadian rhythms are driven by an endogenous central clock in the brain that synchronizes with clocks in peripheral tissues, thereby regulating our immune system and the severity of infections. These rhythms affect the pharmacokinetics and efficacy of therapeutic agents and vaccines. The core circadian regulatory circuits and clock-regulated host pathways provide fertile ground to identify novel antiviral therapies. An increased understanding of the role circadian systems play in regulating virus infection and the host response to the virus will inform our clinical management of these diseases. This review provides an overview of the experimental and clinical evidence reporting on the interplay between the circadian clock and viral infections, highlighting the importance of virus-clock research.

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Circadian clock-controlled drug metabolism and transport

Cited by 25 publications

References 99 publications

Circadian Clock–Controlled Drug Metabolism: Implications for Chronotherapeutics

Circadian Clock–Controlled Drug Metabolism: Implications for Chronotherapeutics

Pharmacokinetics-Based Chronoefficacy of Semen Strychni and Tripterygium Glycoside Tablet Against Rheumatoid Arthritis

The Circadian Clock and Viral Infections

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