Background: The molecular circadian clock, driven by the transcriptional-translational feedback loop (TTFL) of CLOCK and BMAL1, orchestrates rhythmic gene expression in virtually every mammalian tissue. Peripheral oscillators in the liver, intestine, kidney, and pancreas generate diurnal variation in drug-metabolizing enzymes and transporters, rendering the pharmacokinetics of molecular interventions — including micronutrients and pharmaceutical compounds — critically dependent on time of administration.
Objective: This clinical review synthesizes current evidence on how CLOCK/BMAL1-driven transcription regulates absorption, distribution, metabolism, and excretion (ADME) of molecular interventions, with specific emphasis on chrononutritional compounds (vitamin D, magnesium) and their interactions with circadian output pathways.
Methods: Narrative review of peer-reviewed literature identified through structured searches of PubMed, Scopus, and Google Scholar, encompassing primary molecular studies, experimental animal models, and clinical trials published through May 2026.
Conclusions: Dosing time is an independent pharmacokinetic variable for a broad spectrum of molecular interventions. Evening administration of vitamin D activates ROR/REV-ERB nuclear receptors in a phase that can compete with melatonin synthesis pathways, while magnesium's GABAergic pharmacodynamics align with the circadian peak of GABA(A) receptor sensitivity in the mid-to-late subjective day. Integration of clock gene biology into prescribing recommendations represents an actionable and underutilized strategy for improving therapeutic indices across clinical practice.
1. Introduction
For most of the history of pharmacology, the question posed about a drug intervention was what — what molecule, what dose, what route. Only rarely was when considered a variable of comparable precision. This conceptual gap persists in contemporary clinical guidelines, where temporal recommendations for supplementation and drug administration are typically reduced to rudimentary proxies: "morning, with food" or "at bedtime to improve tolerability." Such language lacks mechanistic grounding and, as accumulating evidence demonstrates, may in certain cases be actively suboptimal.
The molecular basis of biological timekeeping was sufficiently understood by 2017 to merit the Nobel Prize in Physiology and Medicine, awarded to Hall, Rosbash, and Young for their elucidation of the Drosophila period gene and its mammalian homologs. In mammals, the central pacemaker resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, entrained primarily by retinal photic input via the retinohypothalamic tract. The SCN synchronizes peripheral clocks in virtually every organ through humoral (glucocorticoids, melatonin), neural (autonomic output), and behavioral (feeding-fasting cycles, locomotion) signals. [^1] Peripheral oscillators are capable of autonomous timekeeping for several cycles, but their phase is reset continuously by these central and environmental zeitgebers.
The TTFL that underlies circadian timekeeping involves the heterodimeric transcription factor CLOCK:BMAL1, which binds E-box promoter elements to drive expression of Per1/2, Cry1/2, Rev-erbα/β, and Rora/b/c. The PER/CRY complex accumulates and subsequently represses CLOCK:BMAL1 activity, completing a 24-hour negative feedback loop. REV-ERBα and REV-ERBβ provide a stabilizing secondary loop by repressing Bmal1 transcription, while RORα activates it. This architecture generates robust, self-sustaining oscillations in the transcription of thousands of clock-controlled genes (CCGs) — estimated at 80–90% of protein-coding genes in at least one tissue. [^2]
Chrononutrition and chronopharmacology represent two faces of the same clinical problem: the extent to which the biological time of administration determines the pharmacokinetic and pharmacodynamic profile of a molecular intervention. This review addresses the mechanistic foundations of that relationship, examines the evidence for specific micronutrients (vitamin D, magnesium), and delineates practical clinical implications for prescribing physicians.
2. Molecular Architecture of Peripheral Circadian Clocks
2.1 The Hepatic Clock
The liver is arguably the most pharmacologically consequential peripheral oscillator, as it houses the primary machinery for Phase I and Phase II drug metabolism, bile acid synthesis, and protein binding of circulating compounds. Approximately 40–50% of hepatic transcripts oscillate with circadian periodicity. Among these are the cytochrome P450 (CYP) enzymes that account for the biotransformation of approximately 70–80% of clinically used drugs. CYP3A4, CYP2E1, CYP7A1 (the rate-limiting enzyme in bile acid synthesis), as well as major Phase II enzymes including sulfotransferases (SULT1A1, SULT1E1) and glutathione S-transferases, exhibit CLOCK/BMAL1-dependent diurnal expression rhythms in rodent and human liver tissue. [^3]
The mechanisms are multilayered. CLOCK:BMAL1 drives rhythmic expression directly via canonical E-box elements in the promoters of CYP genes, and indirectly via clock-controlled nuclear receptors: hepatocyte nuclear factor 4α (HNF4α) and peroxisome proliferator-activated receptor γ (PPARγ) are themselves CCGs whose oscillatory activity amplifies or gates the rhythms of downstream metabolic enzymes. [^4] Additionally, D-box and Rev-erb response elements (RevREs/ROREs) allow PER/CRY repressors and REV-ERBα/RORα to exert further temporal shaping on enzyme expression independently of the E-box pathway, creating a three-axis transcriptional control system.
Guan and colleagues, publishing in Science (2020), demonstrated in a mouse model with hepatocyte-specific deletion of REV-ERBα and REV-ERBβ that the hepatocyte clock not only regulates intrinsic hepatocyte rhythms but communicates temporal information to non-hepatocytic cells including Kupffer cells and stellate cells within the liver. [^5] Manella et al. (Nature Metabolism, 2021) extended this principle, demonstrating that the liver clock buffers feeding-related circadian perturbations and modulates the transcriptional rhythmicity of other peripheral tissues. [^6] These findings underscore the liver's role as a master peripheral oscillator — a hub that integrates nutritional timing signals and propagates temporal information systemically.
2.2 Intestinal and Renal Oscillators
Drug absorption begins in the gastrointestinal tract, and both the rate and extent of absorption vary with time of day. Gastric emptying rate, intestinal motility, luminal pH, mucosal blood flow, and splanchnic perfusion all exhibit circadian variation under clock gene control. Of particular pharmacological significance is the circadian rhythmicity of drug transporters, including the efflux transporters P-glycoprotein (P-gp, ABCB1) and multidrug resistance-associated protein 2 (MRP2, ABCC2) in the intestinal epithelium, and the uptake transporters of the SLC and ABC families in hepatic and renal tissues. [^7] Pàcha et al. (2020) reviewed evidence that diurnal changes in these transporters exert measurable effects on drug pharmacokinetics and noted that the molecular coupling between CLOCK/BMAL1 activity and transporter gene transcription has been demonstrated via E-box elements in the promoters of several key transporters. [^8]
In the kidney, glomerular filtration rate, renal plasma flow, and tubular secretory capacity all follow circadian patterns, contributing to diurnal variation in drug elimination half-life. The circadian control of blood-brain barrier efflux transporters has also been described, with implications for central nervous system drug delivery. [^9]
2.3 The Pancreatic Clock
The endocrine pancreas harbors a self-sustaining clock in which CLOCK and BMAL1 regulate insulin secretion and β-cell glucose sensitivity. Vieira, Burris, and Quesada (Trends in Molecular Medicine, 2014) reviewed evidence that CLOCK-deficient mice exhibit impaired first-phase insulin secretion, reduced expression of Pdx1 (a master transcriptional regulator of β-cell identity), and progressive β-cell failure — recapitulating several features of type 2 diabetes mellitus. [^10] The pancreatic clock's sensitivity to feeding-derived temporal cues means that the timing of carbohydrate ingestion acutely resets the phase of Bmal1 and Per2 expression in islet cells, with downstream effects on the amplitude of insulin secretory responses. This provides part of the mechanistic rationale for chrononutritional strategies in metabolic disease management.
3. Molecular Mechanisms of Chronopharmacokinetics
Dallmann, Okyar, and Lévi (Trends in Molecular Medicine, 2016), in a seminal review drawing on over two decades of chronopharmacology research, formalized the concept that "dosing-time makes the poison" — encapsulating the principle that the time of drug administration can be as clinically relevant as which drug is chosen, particularly for compounds with narrow therapeutic windows or time-sensitive targets. [^11]
The mechanistic dimensions of chronopharmacokinetics can be organized around the four ADME components:
Absorption
Morning oral dosing of many lipophilic drugs yields higher peak plasma concentrations (Cmax) and shorter time to peak (tmax) compared with evening dosing. This reflects higher morning values of gastric acid secretion, gastrointestinal motility, and splanchnic blood flow. Lemmer (1999) reviewed cross-over pharmacokinetic studies demonstrating that this pattern holds for nifedipine, isosorbide-5-mononitrate, propranolol, and several other cardiovascular agents. The effect is largely abolished by sustained-release formulations, confirming that the variation arises from gastrointestinal physiology rather than intrinsic pharmacological properties of the compound.
Distribution
Circadian variation in plasma protein concentrations (albumin, α1-acid glycoprotein) and tissue blood flow alter the volume of distribution for highly protein-bound drugs. Adipose and muscle tissue blood flow exhibit peak values in the subjective afternoon, influencing the tissue distribution of lipophilic compounds.
Metabolism
The rhythmic expression of hepatic CYP enzymes — peaking in the active phase (early morning in humans, early dark phase in nocturnal rodents) — generates predictable diurnal variation in first-pass effect and systemic clearance. Lu et al. (Drug Metabolism and Disposition, 2020) reviewed the evidence that CLOCK:BMAL1 directly targets E-box elements in promoters of CYP1A2, CYP2B6, CYP3A4, SULT1E1, and several other enzymes, and that loss-of-function clock mutations markedly flatten their rhythmic expression and alter the pharmacokinetics of substrate drugs in rodent models. [^4]
Excretion
Renal excretion of drugs is modulated by the circadian rhythm in glomerular filtration rate (highest in the afternoon in humans), urinary pH (lowest in the morning), and tubular transporter activity. Bicker et al. (British Journal of Pharmacology, 2020) provided an updated analysis of circadian control of renal elimination, noting that circadian variation in OAT1/OAT3 (organic anion transporters) and OCT2 (organic cation transporter 2) activity contributes to time-of-day differences in the elimination of renally cleared drugs including methotrexate and cisplatin. [^12]
Yu et al. (Biochemical Pharmacology, 2022) synthesized these mechanisms in an integrative framework, proposing that circadian-regulated pharmacokinetics represent the primary mechanistic substrate through which circadian clock disruption (as occurs in shift work, transmeridian travel, or social jet lag) alters therapeutic drug exposure and toxicity profiles. [^13]
4. Chrononutrition: Feeding as a Zeitgeber for Peripheral Clocks
Oike, Oishi, and Kobori (Current Nutrition Reports, 2014) established that feeding-fasting cycles constitute the dominant synchronizing signal for peripheral clocks, capable of uncoupling hepatic, pancreatic, and adipose circadian phase from the SCN pacemaker when feeding is shifted to the rest phase. [^14] This decoupling — in which the central pacemaker remains entrained to light-dark cycles while peripheral oscillators adopt new phases driven by meal timing — creates internal circadian misalignment that metabolic phenotyping studies consistently associate with insulin resistance, dyslipidemia, and weight gain.
Johnston et al. (Advances in Nutrition, 2016) reviewed human chrononutrition evidence, concluding that time-restricted eating aligned with the active phase (morning and midday) amplifies hepatic Bmal1 expression amplitude and improves metabolic outcomes compared with calorically identical feeding during the late active or rest phase. [^15] The liver clock plays a central integrative role: Tahara and Shibata (Nature Reviews Gastroenterology & Hepatology, 2016) reviewed evidence that food-induced insulin release directly resets the phase of the hepatic clock via phosphorylation of the TTFL components, acting as a rapid molecular zeitgeber. [^16]
For the physician, the implication is that the chrononutritional properties of a supplement or nutraceutical cannot be decoupled from the metabolic context of administration: the same compound ingested in a postprandial state at 08:00 versus a postprandial state at 22:00 encounters a qualitatively different hepatic transcriptional environment, with downstream consequences for its biotransformation, receptor interaction, and downstream signaling.
5. Case Studies in Chronopharmacology of Molecular Interventions
5.1 Vitamin D and the Circadian Clock: A Bidirectional Interaction
Vitamin D3 (cholecalciferol) and its bioactive metabolite 1α,25-dihydroxyvitamin D3 (calcitriol) have historically been discussed almost exclusively in terms of calcium-phosphate homeostasis. The integration of vitamin D signaling into the circadian network represents a more recently recognized and clinically consequential dimension.
Vitamin D as a clock gene modulator.
Gutiérrez-Monreal et al. (Journal of Biological Rhythms, 2014) demonstrated that 1α,25-(OH)₂D3 synchronizes BMAL1 and PER2 expression rhythms in adipose-derived stem cells, with a synchronizing capacity comparable to serum shock — a standard laboratory zeitgeber. [^17] The mechanism involves direct vitamin D receptor (VDR) binding to vitamin D response elements (VDREs) in the promoters of clock genes, as well as indirect modulation through VDR-driven changes in RORα, RORγ, and REV-ERBα activity — proteins that constitute the secondary feedback loop of the TTFL. Slominski et al. (FASEB Journal, 2025) provided molecular evidence that D3 hydroxyderivatives act as inverse agonists on RORα/γ and can directly regulate Clock, Bmal1, and Per1 transcription via RORE elements. [^18]
Vitamin D, melatonin, and the timing problem.
Melatonin synthesis in the pineal gland is itself a circadian output, driven by SCN-mediated noradrenergic stimulation that begins at dusk. The critical step — arylalkylamine N-acetyltransferase (AANAT) activity — is suppressed by light exposure and exhibits peak activity in the early biological night. VDR is expressed in the SCN, and emerging evidence reviewed by Vesković et al. (International Journal of Molecular Sciences, 2026) suggests that calcitriol modulates melatonin synthesis indirectly by altering the transcriptional activity of ROR receptors that regulate Bmal1 — which in turn gates pineal clock-controlled melatonin synthetic enzyme expression. [^19] When vitamin D is administered in the evening, the simultaneous elevation of calcitriol and activation of ROR/REV-ERB-mediated transcriptional programs could potentially phase-shift or attenuate the normal rise in SCN-driven AANAT activity. A 2025 intervention study by Maissan and Carlberg (Nutrients) identified 87 vitamin D target genes with circadian expression patterns in immune cells, revealing that 80% of these genes are downregulated upon vitamin D3 supplementation, and that individual responsiveness varies substantially — a finding with direct implications for personalized timing recommendations. [^20]
From a clinical standpoint, the evidence for dramatic melatonin suppression by evening vitamin D remains mechanistically plausible but not yet definitively demonstrated in controlled human trials. Sanchez (2004, Pediatric Nephrology) raised the possibility that evening dosing of active vitamin D might be preferable for PTH suppression but noted that circadian interaction with melatonin pathways was an open question. [^21] Gray et al. (American Physiology Summit 2025) supplemented participants with 4,000 IU vitamin D3 daily for four weeks and observed reductions in total sleep time and improvements in subjective sleep quality, but did not find significant alterations in canonical circadian parameters (amplitude, acrophase, mesor) — leaving the magnitude of functional circadian interference uncertain.
Clinical recommendation rationale:
Until controlled studies clarify the degree of melatonin pathway interference, morning or early afternoon vitamin D supplementation aligns with endogenous D3 synthesis rhythms (UV-B exposure occurs during daylight hours), preserves the temporal separation from the onset of melatonin synthesis, and exploits peak hepatic CYP27B1 activity that falls within the first half of the active phase. Routine evening supplementation lacks mechanistic justification and carries a theoretically suboptimal interaction profile.
5.2 Magnesium, the GABAergic System, and Circadian Rhythmicity
Magnesium's pharmacological relevance to the circadian system is multidimensional: it is a required cofactor for BMAL1-driven transcriptional activity (as a metal cofactor for Mg2+-dependent ATPases involved in TTFL function), a modulator of NMDA receptor activity (relevant to SCN photic entrainment signaling), and a regulator of GABA(A) receptor function.
The GABAergic circadian system.
GABA is the principal inhibitory neurotransmitter of the SCN, present in the vast majority of SCN neuronal somata and synaptic terminals. The SCN's circadian timekeeping is substantially maintained by astrocytically regulated extracellular GABA concentrations: Patton et al. (PNAS, 2023) demonstrated, using the iGABASnFR sensor, that extracellular GABA in SCN slices oscillates in circadian antiphase to neuronal activity, peaking during circadian night when neuronal firing is low. Astrocytic GABA transporter 3 (GAT3, encoded by Slc6a11 — a CLOCK-controlled gene) mediates GABA clearance during the circadian day, thereby facilitating the high daytime neuronal firing rate characteristic of the SCN. [^22] Cardinali and Golombek (Neurochemical Research, 1998) had earlier established that the GABAergic system exhibits strong diurnal variation in turnover, receptor affinity, and postsynaptic chloride channel activity, and that pharmacological modulation of GABA(A) receptors phase-shifts circadian rhythms. [^23]
Wagner et al. (Nature, 1997) documented a remarkable diurnal switch in GABA's functional polarity in SCN neurons: GABA acts as an inhibitory neurotransmitter at night and as an excitatory neurotransmitter during the day, a reversal mediated by oscillation in intracellular chloride concentration. This indicates that GABAergic pharmacodynamics are fundamentally time-dependent at the level of receptor-effector coupling, not merely at the level of ligand availability.
Magnesium as a chronopharmacological agent
Magnesium modulates GABA(A) receptor function partly through allosteric interactions and partly through its role as an intracellular Mg²⁺ species that participates in intracellular chloride homeostasis (via Mg²⁺-ATPase-dependent cation cotransporters). Given that GABAergic receptor sensitivity peaks during the active phase — corresponding to the mid-to-late subjective afternoon in humans — magnesium supplementation targeted to the second half of the active day aligns with the period of maximal GABAergic receptor responsiveness and optimal coupling of Mg²⁺-dependent processes. The diurnal stability of cortical GABA concentrations documented by Evans et al. (Journal of Magnetic Resonance Imaging, 2009) using edited MRS in healthy humans suggests that total GABA levels vary less dramatically across the day than receptor sensitivity does, further supporting the relevance of timing supplementation to align with receptor-level rather than ligand-level rhythm. [^2]
Additionally, magnesium's role as a cofactor in CYP450-dependent reactions, ATP synthesis, and DNA repair pathways — all of which peak during the active phase under clock gene control — provides converging mechanistic support for mid-to-late afternoon supplementation as the period of maximal biological utilization.
6. Clinical and Translational Implications
6.1 The Gap Between Chronobiology and Clinical Guidelines
Ohdo et al. (Journal of Pharmaceutical Sciences, 2011) observed that CLOCK gene polymorphisms contribute to interindividual variation in pharmacokinetic parameters that are currently attributed to poorly understood sources of intraindividual and interindividual variability. [^24] This has a direct implication: therapeutic drug monitoring, dose optimization, and adverse effect surveillance should in principle account for the circadian phase of sampling and administration — yet this is not routine practice. The prescribing habits that dominate clinical medicine today reflect a pharmacology developed largely without chronobiological awareness.
Paschos, Baggs, Hogenesch, and FitzGerald (Annual Review of Pharmacology and Toxicology, 2010) reviewed diurnal variations in drug absorption, distribution, metabolism, and excretion across four decades of research and concluded that time-of-day is a consistent modulator of pharmacological efficacy that deserves explicit incorporation into clinical trial design and regulatory guidance. [^8] The practical challenges — including interindividual variation in circadian phase (chronotype), shift work disruption, age-related amplitude dampening of clock gene expression, and the complexity of dosing schedules — remain genuine barriers, but they argue for better phenotyping and personalization rather than for ignoring the variable.
Weger, Weger, and Gachon (Expert Opinion on Drug Discovery, 2023) highlighted that sex-related differences in circadian metabolism, feeding behavior rhythms, and gut microbiota composition all modify chronopharmacological responses, and argued that these covariates are systematically overlooked in drug discovery pipelines. [^25]
6.2 Toward Rational Prescribing of Molecular Interventions by Circadian Phase
A summary of practical timing recommendations grounded in the mechanistic evidence reviewed above:
| Molecular Intervention | Recommended Timing Window | Primary Mechanistic Rationale |
|---|---|---|
| Vitamin D3 (cholecalciferol) | Morning to early afternoon (08:00–14:00) | Aligns with endogenous synthesis rhythm; avoids overlap with melatonin synthesis phase; exploits peak hepatic 25-hydroxylase (CYP2R1) activity |
| Magnesium (glycinate, malate) | Mid-to-late afternoon (14:00–18:00) | Aligns with peak GABA(A) receptor sensitivity window; coincides with active-phase peak of Mg²⁺-dependent enzymatic pathways |
| HMG-CoA reductase inhibitors (statins) | Evening (statins with short half-life) | Hepatic cholesterol synthesis peaks during the biological night; evening dosing maximizes temporal overlap with target activity |
| Corticosteroids | Early morning (06:00–08:00) | Mimics endogenous cortisol peak; minimizes HPA axis suppression; aligns with peak glucocorticoid receptor expression |
| Methotrexate (oncological) | Afternoon to early evening | Targets S-phase fraction of cycling cells, which peak in the biological afternoon; reduces renal toxicity |
Table 1. Illustrative chronopharmacological timing rationale for selected molecular interventions. Evidence strength varies across compounds; timing recommendations should be individualized for chronotype, metabolic status, and comorbidity.
6.3 Personalized Chronotherapy: Emerging Tools
Shrivastava et al. (Archives of Current Research International, 2026) outlined emerging technologies enabling individualized chronotherapy, including wearable-derived circadian phase markers (wrist temperature, activity rhythm actigraphy), digital phenotyping of sleep-wake behavior as a chronotype proxy, and multi-omics integration of transcriptomic and metabolomic circadian profiles. The practical ambition is to move beyond population-level timing recommendations to individualized prescribing windows informed by the patient's actual circadian phase — particularly relevant in oncology (where circadian-guided chemotherapy has shown the most robust clinical evidence to date) and in metabolic medicine.
7. Conclusion
The circadian clock is not a peripheral curiosity of chronobiology — it is a pervasive, molecularly precise regulator of the pharmacological behavior of virtually every class of molecular intervention, from prescription drugs to nutritional supplements. CLOCK and BMAL1, through their control of CYP enzymes, drug transporters, nuclear receptors, and downstream metabolic pathways in liver, intestine, kidney, and pancreas, impose robust diurnal periodicity on ADME parameters. This periodicity is actionable: it can be exploited to improve therapeutic efficacy, reduce toxicity, and optimize the pharmacodynamic response of molecular interventions.
For the practicing clinician, three principles emerge from this body of evidence.
- First, prescribing "when" deserves the same precision as prescribing "what" and "how much" — at minimum for compounds with significant first-pass hepatic metabolism, narrow therapeutic windows, or pharmacodynamic targets known to exhibit circadian expression rhythms.
- Second, the peripheral clock in the liver and pancreas is itself entrained by meal timing, meaning that dietary prescriptions and supplement timing interact mechanistically, not merely logistically.
- Third, specific molecular interactions — such as vitamin D3's bidirectional relationship with clock gene expression via VDR/ROR/REV-ERB signaling, and magnesium's alignment with the circadian peak of GABAergic receptor sensitivity — provide mechanistic rationale for timing recommendations that go beyond generic guidance.
The field of chronopharmacology is sufficiently mature to support evidence-based revisions to clinical practice guidelines. Integrating circadian biology into prescribing education, drug labeling, and clinical trial design represents a tractable and high-yield opportunity to improve patient outcomes without modifying the molecules themselves — by simply asking, with greater precision, when.
1. Musiek E, FitzGerald G. Molecular clocks in pharmacology. Handbook of Experimental Pharmacology. 2013. DOI: 10.1007/978-3-642-25950-010 [^1] 2. Dallmann R, Okyar A, Lévi F. Dosing-Time Makes the Poison: Circadian Regulation and Pharmacotherapy. Trends in Molecular Medicine. 2016;22:430–445. [^11] 3. Lu D, Zhao M, Chen M, Wu B. Circadian Clock–Controlled Drug Metabolism: Implications for Chronotherapeutics. Drug Metabolism and Disposition. 2020;48(5):395–406. [^4] 4. Zhao M, Xing H, Chen M, Dong D, Wu B. Circadian clock-controlled drug metabolism and transport. Xenobiotica. 2020;50(1):20–34. [^7] 5. Pácha J, Balounová K, Sotàk M. Circadian regulation of transporter expression and implications for drug disposition. Expert Opinion on Drug Metabolism & Toxicology. 2020. [^8] 6. Okyar A, Ozturk Civelek D, Akyel Y, et al. The role of the circadian timing system on drug metabolism and detoxification: an update. Expert Opinion on Drug Metabolism & Toxicology. 2024. [^9] 7. Guan D, Xiong Y, Trinh TM, et al. The hepatocyte clock and feeding control chronophysiology of multiple liver cell types. Science. 2020;371(6530):1388–1393. [^5] 8. Manella G, Sabath E, Aviram R, et al. The liver-clock coordinates rhythmicity of peripheral tissues in response to feeding. Nature Metabolism. 2021;3:829–842. [^6] 9. Vieira E, Burris TP, Quesada I. Clock genes, pancreatic function, and diabetes. Trends in Molecular Medicine. 2014;20(12):685–693. [^10] 10. Bicker J, Alves G, Falcão A, Fortuna A. Timing in drug absorption and disposition: The past, present, and future of chronopharmacokinetics. British Journal of Pharmacology. 2020;177(10):2215–2239. [^12] 11. Yu F, Liu Y, Zhang R, et al. Recent advances in circadian-regulated pharmacokinetics and its implications for chronotherapy. Biochemical Pharmacology. 2022;204:115185. [^13] 12. Lemmer B. Chronopharmacokinetics: Implications for Drug Treatment. Journal of Pharmacy and Pharmacology. 1999;51(8):887–890. 13. Oike H, Oishi K, Kobori M. Nutrients, Clock Genes, and Chrononutrition. Current Nutrition Reports. 2014;3(3):204–212. [^14] 14. Johnston JD, Ordovás JM, Scheer FA, Turek FW. Circadian Rhythms, Metabolism, and Chrononutrition in Rodents and Humans. Advances in Nutrition. 2016;7(2):399–406. [^15] 15. Tahara Y, Shibata S. Circadian rhythms of liver physiology and disease: experimental and clinical evidence. Nature Reviews Gastroenterology & Hepatology. 2016;13(4):217–226. [^16] 16. Gutiérrez-Monreal MA, Cuevas-Díaz Durán R, Moreno-Cuevas JE, Scott SP. A Role for 1α,25-Dihydroxyvitamin D3 in the Expression of Circadian Genes. Journal of Biological Rhythms. 2014;29(5):384–388. [^17] 17. Slominski AT, Slominski RM, Kamal M, et al. Is Vitamin D Signaling Regulated by and Does It Regulate Circadian Rhythms? FASEB Journal. 2025. DOI: 10.1096/fj.202503003R [^18] 18. Vesković M, Šutulović N, Đurić E, et al. Vitamin D as a Regulator of the Biological Clock — Implications for Circadian-Metabolic Dysregulation. International Journal of Molecular Sciences. 2026;27(7):3243. [^19] 19. Maissan P, Carlberg C. Circadian Regulation of Vitamin D Target Genes Reveals a Network Shaped by Individual Responsiveness. Nutrients. 2025;17(7):1204. [^20] 20. Patton AP, Morris EL, McManus D, et al. Astrocytic control of extracellular GABA drives circadian timekeeping in the suprachiasmatic nucleus. PNAS. 2023;120(41):e2301330120. [^22] 21. Cardinali DP, Golombek DA. The Rhythmic GABAergic System. Neurochemical Research. 1998;23(5):607–614. [^23] 22. Wagner S, Castel M, Gainer H, Yarom Y. GABA in the mammalian suprachiasmatic nucleus and its role in diurnal rhythmicity. Nature. 1997;387(6633):598–603. 23. Ohdo S, Koyanagi S, Matsunaga N, Hamdan A. Molecular basis of chronopharmaceutics. Journal of Pharmaceutical Sciences. 2011;100(9):3560–3576. [^24] 24. Paschos GK, Baggs JE, Hogenesch JB, FitzGerald GA. The role of clock genes in pharmacology. Annual Review of Pharmacology and Toxicology. 2010;50:187–214. [^8] 25. Weger BD, Weger M, Gachon F. Understanding circadian dynamics: current progress and future directions for chronobiology in drug discovery. Expert Opinion on Drug Discovery. 2023;18(10):1109–1119. [^25] 26. Shrivastava A, Shrivastava N, Chatur Y, et al. Chrono-Pharmacology in the Era of Precision Medicine: Mechanisms, Clinical Evidence, and Translational Perspectives. Archives of Current Research International. 2026.
Disclosure: The author declares no conflicts of interest. No external funding was received for the preparation of this manuscript.
Word count (body text, excluding abstract and references): approximately 4,600 words
[^1]: Musiek & FitzGerald, 2013. Molecular clocks in pharmacology. Handbook of Experimental Pharmacology.
[^2]: Ohdo et al., 2011. Molecular basis of chronopharmaceutics. Journal of Pharmacy and Science.
[^3]: Lu et al., 2020. Circadian Clock–Controlled Drug Metabolism: Implications for Chronotherapeutics. Drug Metabolism And Disposition.
[^4]: Guan et al., 2020. The hepatocyte clock and feeding control chronophysiology of multiple liver cell types. Science.
[^5]: Manella et al., 2021. The liver-clock coordinates rhythmicity of peripheral tissues in response to feeding. Nature Metabolism.
[^6]: Zhao et al., 2020. Circadian clock-controlled drug metabolism and transport. Xenobiotica; the fate of foreign compounds in biological systems.
[^7]: Pácha et al., 2020. Circadian regulation of transporter expression and implications for drug disposition. Expert Opinion on Drug Metabolism & Toxicology.
[^8]: Okyar et al., 2024. The role of the circadian timing system on drug metabolism and detoxification: an update. Expert Opinion on Drug Metabolism & Toxicology.
[^9]: Vieira et al., 2014. Clock genes, pancreatic function, and diabetes. Trends in Molecular Medicine.
[^10]: Dallmann et al., 2016. Dosing-Time Makes the Poison: Circadian Regulation and Pharmacotherapy. Trends in Molecular Medicine.
[^11]: Lemmer, 1999. Chronopharmacokinetics: Implications for Drug Treatment. The Journal of pharmacy and pharmacology.
[^12]: Yu et al., 2022. Recent advances in circadian-regulated pharmacokinetics and its implications for chronotherapy. Biochemical Pharmacology.
[^13]: Oike et al., 2014. Nutrients, Clock Genes, and Chrononutrition. Current nutrition reports.
[^14]: Johnston et al., 2016. Circadian Rhythms, Metabolism, and Chrononutrition in Rodents and Humans. Advances in Nutrition.
[^15]: Tahara & Shibata, 2015. Nutrition and Diet as Potent Regulators of the Liver Clock.
[^16]: Gutiérrez-Monreal et al., 2014. A Role for 1α,25-Dihydroxyvitamin D3 in the Expression of Circadian Genes. Journal of Biological Rhythms.
[^17]: Slominski et al., 2025. Is Vitamin D Signaling Regulated by and Does It Regulate Circadian Rhythms?. The FASEB Journal.
[^18]: Vesković et al., 2026. Vitamin D as a Regulator of the Biological Clock—Implications for Circadian–Metabolic Dysregulation. International Journal of Molecular Sciences.
[^19]: Maissan & Carlberg, 2025. Circadian Regulation of Vitamin D Target Genes Reveals a Network Shaped by Individual Responsiveness. Nutrients.
[^20]: Sanchez, 2004. Chronotherapy of high-dose active vitamin D3: is evening dosing preferable?. Pediatric nephrology (Berlin, West).
[^21]: Gray et al., 2025. The Effect of Vitamin D Supplementation on Circadian Rhythms and Sleep. Physiology.
[^22]: Cardinali & Golombek, 1998. The Rhythmic GABAergic System. Neurochemical Research.
[^23]: Wagner et al., 1997. GABA in the mammalian suprachiasmatic nucleus and its role in diurnal rhythmicity. Nature.
[^24]: Paschos et al., 2010. The role of clock genes in pharmacology. Annual Review of Pharmacology and Toxicology.
[^25]: Shrivastava et al., 2026. Chrono-Pharmacology in the Era of Precision Medicine: Mechanisms, Clinical Evidence, and Translational Perspectives. Archives of Current Research International.
