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![PBPK model simulations of plasma and tissue concentration–time profiles of an oral administration of three-times daily 1000 mg metformin (highest recommended dose according to the German prescribing information [21]) at 07:00, 15:00 and 23:00 hours (indicated by arrows). (a–e) Comparison of metformin levels in (a) plasma, (b) kidney tissue, (c) liver tissue, (d) fat tissue and (e) muscle tissue. Respective simulations with a mean parameter set of OCT2 kcat, amplitude and acrophase are shown as dark lines, simulations with individual parameter sets (n=26) are shown as light lines. Grey areas indicate night-time. (f) Comparison of metformin peak-to-trough ratios for simulations in plasma and tissues. The three box plots per tissue give peak-to-trough ratios after metformin administration at 07:00, 15:00 and 23:00 hours. Dots (peak 1), triangles (peak 2) and squares (peak 3) show individual peak-to-trough ratios (n=26), crosses indicate mean values. Boxes represent the distance between first and third quartiles (IQR). Whiskers range from smallest to highest value (<1.5 × IQR)](publication/369331808/figure/fig4/AS:11431281156053656@1683337770361/PBPK-model-simulations-of-plasma-and-tissue-concentration-time-profiles-of-an-oral.png)
PBPK model simulations of plasma and tissue concentration–time profiles of an oral administration of three-times daily 1000 mg metformin (highest recommended dose according to the German prescribing information [21]) at 07:00, 15:00 and 23:00 hours (indicated by arrows). (a–e) Comparison of metformin levels in (a) plasma, (b) kidney tissue, (c) liver tissue, (d) fat tissue and (e) muscle tissue. Respective simulations with a mean parameter set of OCT2 kcat, amplitude and acrophase are shown as dark lines, simulations with individual parameter sets (n=26) are shown as light lines. Grey areas indicate night-time. (f) Comparison of metformin peak-to-trough ratios for simulations in plasma and tissues. The three box plots per tissue give peak-to-trough ratios after metformin administration at 07:00, 15:00 and 23:00 hours. Dots (peak 1), triangles (peak 2) and squares (peak 3) show individual peak-to-trough ratios (n=26), crosses indicate mean values. Boxes represent the distance between first and third quartiles (IQR). Whiskers range from smallest to highest value (<1.5 × IQR)
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Aims/hypothesis
The objective was to investigate if metformin pharmacokinetics is modulated by time-of-day in humans using empirical and mechanistic pharmacokinetic modelling techniques on a large clinical dataset. This study also aimed to generate and test hypotheses on the underlying mechanisms, including evidence for chronotype-dependent interin...
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Citations
... In terms of pharmacological treatment, even though the evidence is still lacking, chronotherapy that consists of optimized circadian rhythm and regulating the timing of drug medications has emerged in various conditions to achieve more treatment efficacy and fewer side effects [119,120]. For example, the experimental studies demonstrated the time-dependent effects of metformin on blood glucose and its interaction with the circadian rhythm [121]. Accordingly, future research is needed to investigate the impact of ALAN on diabetes medication strategies in patients with T2DM through clinical trials, considering that both are influenced by circadian rhythm. ...
The widespread and pervasive use of artificial light at night (ALAN) in our modern 24-hour society has emerged as a substantial disruptor of natural circadian rhythms, potentially leading to a rise in unhealthy lifestyle-related behaviors (e.g., poor sleep; shift work). This phenomenon has been associated with an increased risk of type 2 diabetes mellitus (T2DM), which is a pressing global public health concern. However, to date, reviews summarizing associations between ALAN and T2DM have primarily focused on the limited characteristics of exposure (e.g., intensity) to ALAN. This literature review extends beyond prior reviews by consolidating recent studies from 2000 to 2024 regarding associations between both indoor and outdoor ALAN exposure and the incidence or prevalence of T2DM. We also described potential biological mechanisms through which ALAN modulates glucose metabolism. Furthermore, we outlined knowledge gaps and investigated how various ALAN characteristics beyond only light intensity (including light type, timing, duration, wavelength, and individual sensitivity) influence T2DM risk. Recognizing the detrimental impact of ALAN on sleep health and the behavioral correlates of physical activity and dietary patterns, we additionally summarized studies investigating the potential mediating role of each component in the relationship between ALAN and glucose metabolism. Lastly, we proposed implications of chronotherapies and chrononutrition for diabetes management in the context of ALAN exposure.
... Finally, renal elimination of drugs, via the regulation of blood flow, tubular secretions, and urinary pH, also contributes to rhythmic variations in the pharmacodynamics of drugs and may be more efficient during the active phase [70]. Chronotherapy has been applied toward the treatment of hypertension and hyperlipidemia [71], major depressive disorder and seasonal affective disorder [72,73], obesity and Type 2 diabetes [74,75], and several cancers [76,77]. Adjusting the timing of therapeutic delivery to match the specific drug target allows for enhanced outcomes and often reduced off-target effects and detrimental side effects. ...
... Chronotherapy has been applied toward the treatment of hypertension and hyperlipidemia [71], major depressive disorder and seasonal affective disorder [72,73], obesity and Type 2 diabetes [74,75], and several cancers [76,77]. Adjusting the timing of therapeutic delivery to match the specific drug target allows for enhanced outcomes and often reduced off-target effects and detrimental side effects. ...
Simple Summary
The circadian clock controls the rhythmic timing of nearly every aspect of physiology, including sleep, body temperature, hormone fluctuation, and overall metabolism on a daily basis. Research shows that disruption to this control contributes to the development of diseases, including cancer. Evidence also suggests that cancers may be amenable to treatments that target the circadian clock, which maximizes benefits while minimizing side effects. Here, the rhythmic influence over cancers of the liver and gut will be reviewed, and treatments that take into account the circadian clock will be discussed.
Abstract
Circadian rhythms dictate the timing of cellular and organismal physiology to maintain homeostasis. Within the liver and gut, circadian rhythms influence lipid and glucose homeostasis, xenobiotic metabolism, and nutrient absorption. Disruption of this orchestrated timing is known to negatively impact human health and contribute to disease progression, including carcinogenesis. Dysfunctional core clock timing has been identified in malignant growths and may be used as a molecular signature of disease progression. Likewise, the circadian clock and its downstream effectors also represent potential for novel therapeutic targets. Here, the role of circadian rhythms in the pathogenesis of cancers of the liver and gut will be reviewed, and chronotherapy and chronopharmacology will be explored as potential treatment options.
... The present protocol substantiates that metformin's toxicity [44] via interactions with the GM potentiated its effect to toxic level. Though, it is well established that Metformin is not metabolized by liver enzymes, but multidrug and toxin extrusion protein 1 (MATE1) expressed in hepatocytes participates in elimination of unchanged drug with the bile or its transport with blood to kidney and is excreted urine [45,46]. Nevertheless, Gut microbes can directly metabolize the drug [47], expressing more than 100-fold genes than the human genomes [48], including many enzymes capable to metabolize the drug [49,50], and consequences of microbiome mediated drug transformation are often distinct from those of liver-enzyme mediated [51]. ...
Cardiovascular diseases (CVD) cause significant global morbidity, mortality and public health burden annually. CVD alters richness, diversity, and composition of Gut microbiota along with RAS and histopathological differences. Present study explores Metformin role in mitigating doxorubicin induced cardiovascular toxicity/ remodeling. Animals were divided into 4 groups with n=6: Group I (N. Control) free access to diet and water; Group II (MET. Control) on oral Metformin (250 mg/kg) daily; Group III (DOX. Control) alternate day intra-peritoneal Doxorubicin (3 mg/kg) totaling 18 mg/kg; Group IV (DOX. MET. Control) received both daily oral Metformin (250 mg/kg) and alternate day Doxorubicin (3 mg/kg). Gut microbial analysis was made from stool before animals were sacrificed for biochemical and histopathological analysis. Significant alterations were observed in ɑ and β-diversity with new genus from Firmicutes, specifically Clostridia_UCG-014, Eubacterium ruminantium, and Tunicibacter, were prevalent in both the DOX. Control and DOX.MET groups. Proteobacteria, represented by Succinivibrio, were absent in all groups. Additionally, Parabacteroides from the Bacteroidia phylum was absent in all groups except the N. control. In the DOX.MET Control group, levels of Angiotensin II (7.75± 0.49 nmol/min, p<0.01) and Renin (2.60±0.26 ng/ml/hr) were significantly reduced. Conversely, levels of CK-MB, Fibrinogen, Troponin, CRP (p < 0.0001), and TNFɑ (p < 0.05) were elevated. Histopathological examination revealed substantial cardiac changes, including Fibrinogen and fat deposition and eosinophilic infiltration , as well as liver damage characterized by binucleated cells and damaged hepatocytes, along with altered renal tissues in the DOX.MET.Control group. The findings suggest that MET. significantly modifies gut micro-biota, particularly impacting the Firmicutes and Proteobacteria phyla. The reduction in Angiotensin II levels, alongside increased inflammatory markers and myocardial damage, highlights the complex interactions and potential adverse effects associated with MET therapy on cardiovascular health.
... MET is mainly cleared (approximately 80%) by renal elimination mediated by OCT2 (expressed on the basolateral membrane of renal tubule cells) into tubule cells and by MATE1 and MATE2 (expressed on the apical membrane of renal tubule cells) into urine [25,34]. MET pharmacokinetics exhibits circadian rhythm dependent on glomerular filtration rate, renal blood flow, and OCT2 transporter activity, with higher values of total apparent clearance (Cl/F) in the morning compared to the evening [40,41]. So, in the present study, all participants received a single oral dose of 50 mg MET in the morning as a probe of OCT1/2 in both phases of the study (Phases 1 and 2). ...
This study aims to evaluate the impact of liver fibrosis stages of chronic infection with hepatitis C virus (HCV) on the in vivo activity of organic cation transporters (hepatic OCT1 and renal OCT2) using metformin (MET) as a probe drug. Participants allocated in Group 1 (n = 15, mild to moderate liver fibrosis) or 2 (n = 13, advanced liver fibrosis and cirrhosis) received a single MET 50 mg oral dose before direct-acting antiviral (DAA) drug treatment (Phase 1) and 30 days after achieving sustained virologic response (Phase 2). OCT1/2 activity (MET AUC0–24) was found to be reduced by 25% when comparing the two groups in Phase 2 (ratio 0.75 (0.61–0.93), p < 0.05) but not in Phase 1 (ratio 0.81 (0.66–0.98), p > 0.05). When Phases 1 and 2 were compared, no changes were detected in both Groups 1 (ratio 1.10 (0.97–1.24), p > 0.05) and 2 (ratio 1.03 (0.94–1.12), p > 0.05). So, this study shows a reduction of approximately 25% in the in vivo activity of OCT1/2 in participants with advanced liver fibrosis and cirrhosis after achieving sustained virologic response and highlights that OCT1/2 in vivo activity depends on the liver fibrosis stage of chronic HCV infection.
... Türk et al showed that daily variations in the pharmacokinetics of metformin among diabetic patients were influenced by circadian rhythms in glomerular filtration rate, renal plasma flow, and the activity of the organic cation transporter 2 (31). This finding emphasizes the importance of considering biological rhythms in optimizing metformin dosing. ...
Aim
To investigate the factors affecting metformin concentrations after chronic administration in patients with polycystic ovary syndrome (PCOS), focusing on the pharmacokinetic variability and its implications for personalized therapy.
Methods
This study enrolled 53 PCOS patients undergoing long-term metformin treatment at the Clinic for Gynecology and Obstetrics in Niš, Serbia, from February to December 2019. Pharmacokinetic parameters were measured from blood samples, and metformin concentrations were determined with validated analytical techniques.
Results
There was a significant variability in metformin concentrations among PCOS patients, with body mass index (BMI) identified as a major influencing factor. Higher BMI was associated with lower plasma metformin levels, a finding suggesting an altered pharmacokinetic profile in obese patients.
Conclusions
This study highlights the critical role of BMI in influencing metformin pharmacokinetics in PCOS patients and underscores the need for personalized treatment strategies in patients with PCOS.
... Moreover, our preliminary results demonstrated that the plasma concentration of metformin was significantly elevated in TAA-induced ALI rats. Normally, metformin is excreted as a prototype and not affected by hepatic metabolism [10], indicating that the absorption or execration of metformin may be altered in rats with liver failure. The alternation of intestinal or renal metformin transporters caused by ALI may be responsible for this change. ...
Metformin plasma exposure is increased in rats with thioacetamide (TAA)-induced liver failure. The absorption, distribution, and excretion process of metformin is mainly mediated by organic cation transporters (OCTs) and multidrug and toxin extrusion transporters (MATEs). To investigate the mechanisms of the increase in TAA-induced metformin plasma exposure, we employed intestinal perfusion and urinary excretion assays to evaluate the changes in the absorption and excretion of metformin and used Western blotting to investigate the metformin-related transport proteins’ expression changes and mechanisms. The results showed that neither intestinal OCT2 expression nor metformin intestinal absorption were significantly altered by TAA-induced liver failure, while significantly decreased expression and function of renal OCT2 and MATE1 as well as impaired metformin excretion were observed in TAA rats. HK-2 cells were used as an in vitro model to explore the mechanism of liver-failure-mediated downregulation in renal OCT2 and MATE1. The results demonstrated that among numerous abnormal substances that changed in acute liver failure, elevated estrogen levels and tumor necrosis factor-α were the main factors mediating the downregulation of OCT2 and MATE1. In conclusion, this study highlights the downregulation of renal OCT2 and MATE1 in liver injury and its regulatory mechanism and reveals its roles in the increase in TAA-mediated metformin plasma exposure.
... Histological examination employing both H&E staining and Masson's trichrome staining further confirmed a substantial reduction in glandular fibrosis by day 12 in the metformin-treated group (p < 0.01), along with mitigation of acinar atrophy ( Figure 5C,D,F). Additionally, given that metformin is primarily metabolized by the kidneys [25], we conducted H&E staining of kidney tissues from each experimental group and found no discernible pathological alterations, indicating that the drug's toxicity at the administered concentration is within the acceptable limits ( Figure 5E). Lastly, IHC analysis indicated that α-SMA (p < 0.05) and TGF-β1 (p < 0.05) expression levels were markedly decreased in the metformin-treated group, corroborating the in vitro findings ( Figure 6A-J). ...
Fibrosis commonly arises from salivary gland injuries induced by factors such as inflammation, ductal obstruction, radiation, aging, and autoimmunity, leading to glandular atrophy and functional impairment. However, effective treatments for these injuries remain elusive. Transforming growth factor-beta 1 (TGF-β1) is fundamental in fibrosis, advancing fibroblast differentiation into myofibroblasts and enhancing the extracellular matrix in the salivary gland. The involvement of the SMAD pathway and reactive oxygen species (ROS) in this context has been postulated. Metformin, a type 2 diabetes mellitus (T2DM) medication, has been noted for its potent anti-fibrotic effects. Through human samples, primary salivary gland fibroblasts, and a rat model, this study explored metformin’s anti-fibrotic properties. Elevated levels of TGF-β1 (p < 0.01) and alpha-smooth muscle actin (α-SMA) (p < 0.01) were observed in human sialadenitis samples. The analysis showed that metformin attenuates TGF-β1-induced fibrosis by inhibiting SMAD phosphorylation (p < 0.01) through adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)-independent pathways and activating the AMPK pathway, consequently suppressing NADPH oxidase 4 (NOX4) (p < 0.01), a main ROS producer. Moreover, in rats, metformin not only reduced glandular fibrosis post-ductal ligation but also protected acinar cells from ligation-induced injuries, thereby normalizing the levels of aquaporin 5 (AQP5) (p < 0.05). Overall, this study underscores the potential of metformin as a promising therapeutic option for salivary gland fibrosis.
... Furthermore, it is worth mentioning that we also characterized the influence of gut microbiota on the seasonal differential effects of proanthocyanidins by at least modulating their bioavailability in diet-induced obese rats [35]. According to these findings, the gut microbiota has also been implicated in significantly impacting the time-of-day variation in the pharmacokinetics of drugs such as metformin, thus modulating host circadian rhythms and metabolic health [72,73]. Consequently, a plausible explanation for the chronotherapeutic behavior of GSPE could involve the daynight differential dynamics of the gut microbiota, which may differentially affect the GSPE bioavailability. ...
Polyphenols play a key role in the modulation of circadian rhythms, while the cafeteria diet (CAF) is able to perturb the hepatic biological rhythm and induce important ROS production. Consequently, we aimed to elucidate whether grape seed proanthocyanidin extract (GSPE) administration recovers the CAF-induced hepatic antioxidant (AOX) misalignment and characterize the chronotherapeutic properties of GSPE. For this purpose, Fischer 344 rats were fed a standard diet (STD) or a CAF and concomitantly treated with GSPE at two time-points (ZT0 vs. ZT12). Animals were euthanized every 6 h and the diurnal rhythms of hepatic ROS-related biomarkers, hepatic metabolites, and AOX gene expression were examined. Interestingly, GSPE treatment was able to recover the diurnal rhythm lost due to the CAF. Moreover, GSPE treatment also increased the acrophase of Sod1, as well as bringing the peak closer to that of the STD group. GSPE also corrected some hepatic metabolites altered by the CAF. Importantly, the differences observed at ZT0 vs. ZT12 due to the time of GSPE administration highlight a chronotherapeutic profile on the proanthocyanin effect. Finally, GSPE could also reduce diet-induced hepatic oxidative stress not only by its ROS-scavenging properties but also by retraining the circadian rhythm of AOX enzymes.
... Metformin drives a phenotypic shift away from fat accumulation via AMPK-NAMPT-SIRT1-mediated alterations in clock components, providing support for chronotherapeutic approaches to the treatment of obesity [172]. Additionally, metformin's human pharmacokinetics are affected by interindividual variation and time of day due to oscillations in glomerular filtration rate (GFR), renal plasma flow (RPF), and organic cation transporter 2 (OCT2) activity, indicating that the individual chronotype may be important for metformin's chronotherapy [173]. ...
Essential for survival and reproduction, the circadian timing system (CTS) regulates adaptation to cyclical changes such as the light/dark cycle, temperature change, and food availability. The regulation of energy homeostasis possesses rhythmic properties that correspond to constantly fluctuating needs for energy production and consumption. Adipose tissue is mainly responsible for energy storage and, thus, operates as one of the principal components of energy homeostasis regulation. In accordance with its roles in energy homeostasis, alterations in adipose tissue’s physiological processes are associated with numerous pathologies, such as obesity and type 2 diabetes. These alterations also include changes in circadian rhythm. In the current review, we aim to summarize the current knowledge regarding the circadian rhythmicity of adipogenesis, lipolysis, adipokine secretion, browning, and non-shivering thermogenesis in adipose tissue and to evaluate possible links between those alterations and metabolic diseases. Based on this evaluation, potential therapeutic approaches, as well as clock genes as potential therapeutic targets, are also discussed in the context of chronotherapy.
