A non-linear pharmacokinetic-pharmacodynamic relationship of metformin in healthy volunteers: An open-label, parallel group, randomized clinical study

Chung, Hyewon; Oh, Jaeseong; Yoon, Seo Hyun; Yu, Kyung‐Sang; Cho, Joo Youn; Chung, Jae Yong

doi:10.1371/journal.pone.0191258

Cited by 20 publications

(33 citation statements)

References 26 publications

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“…30 This is especially so at higher metformin doses, consistent with a local antihyperglycaemic effect of unabsorbed metformin within the intestine. 30 In addition, metformin is known to accumulate in intestinal tissues after dosing, as described above. These observations are consistent with a clinically significant antihyperglycaemic action of metformin in the gut.…”

Section: Intestinal Disposal Of Glucosementioning

confidence: 66%

“…Clinical studies have confirmed that the antihyperglycaemic action of immediate‐release or prolonged‐release metformin on blood glucose is dose‐dependent but not related clearly to systemic exposure to metformin, as measured by plasma concentration‐time curves . This is especially so at higher metformin doses, consistent with a local antihyperglycaemic effect of unabsorbed metformin within the intestine . In addition, metformin is known to accumulate in intestinal tissues after dosing, as described above.…”

Section: Antihyperglycaemic Mechanismsmentioning

confidence: 99%

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Mechanisms of action of metformin with special reference to cardiovascular protection

Zilov

Abdelaziz

Alshammary

et al. 2019

Diabetes Metabolism Res

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Summary Management guidelines continue to identify metformin as initial pharmacologic antidiabetic therapy of choice for people with type 2 diabetes without contraindications, despite recent randomized trials that have demonstrated significant improvements in cardiovascular outcomes with newer classes of antidiabetic therapies. The purpose of this review is to summarize the current state of knowledge of metformin's therapeutic actions on blood glucose and cardiovascular clinical evidence and to consider the mechanisms that underlie them. The effects of metformin on glycaemia occur mainly in the liver, but metformin‐stimulated glucose disposal by the gut has emerged as an increasingly import site of action of metformin. Additionally, metformin induces increased secretion of GLP‐1 from intestinal L‐cells. Clinical cardiovascular protection with metformin is supported by three randomized outcomes trials (in newly diagnosed and late stage insulin‐treated type 2 diabetes patients) and a wealth of observational data. Initial evidence suggests that cotreatment with metformin may enhance the impact of newer incretin‐based therapies on cardiovascular outcomes, an important observation as metformin can be combined with any other antidiabetic agent. Multiple potential mechanisms support the concept of cardiovascular protection with metformin beyond those provided by reduced blood glucose, including weight loss, improvements in haemostatic function, reduced inflammation, and oxidative stress, and inhibition of key steps in the process of atherosclerosis. Accordingly, metformin remains well placed to support improvements in cardiovascular outcomes, from diagnosis and throughout the course of type 2 diabetes, even in this new age of improved outcomes in type 2 diabetes.

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Section: Intestinal Disposal Of Glucosementioning

confidence: 66%

Section: Antihyperglycaemic Mechanismsmentioning

confidence: 99%

Mechanisms of action of metformin with special reference to cardiovascular protection

Zilov

Abdelaziz

Alshammary

et al. 2019

Diabetes Metabolism Res

View full text Add to dashboard Cite

show abstract

“…Pharmacokinetic parameters can be modified after two different secondary doses of metformin (250 or 1000 mg). In this case, C max varied from 591.1 ± 247.5 to 1937.5 ± 863.0 µg/ml), whereas T max and t 1/2 did not show dose-dependent changes ( Chung et al., 2018 ). A recent study showed that high-intensity interval exercise diminishes metformin concentration (2–3 h), increases C max (4.4 ± 2.5 µg/ml) and diminishes T max (2.7 ± 0.9 h) ( Nikolaidis et al., 2020 ).…”

Section: Pharmacokinetics Of Metforminmentioning

confidence: 76%

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

et al. 2020

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Metformin (biguanide) is a drug widely used for the treatment of type 2 diabetes. This drug has been used for 60 years as a highly effective antihyperglycemic agent. The search for the mechanism of action of metformin has produced an enormous amount of research to explain its effects on gluconeogenesis, protein metabolism, fatty acid oxidation, oxidative stress, glucose uptake, autophagy and pain, among others. It was only up the end of the 1990s and beginning of this century that some of its mechanisms were revealed. Metformin induces its beneficial effects in diabetes through the activation of a master switch kinase named AMP-activated protein kinase (AMPK). Two upstream kinases account for the physiological activation of AMPK: liver kinase B1 and calcium/ calmodulin-dependent protein kinase kinase 2. Once activated, AMPK inhibits the mechanistic target of rapamycin complex 1 (mTORC1), which in turn avoids the phosphorylation of p70 ribosomal protein S6 kinase 1 and phosphatidylinositol 3kinase/protein kinase B signaling pathways and reduces cap-dependent translation initiation. Since metformin is a disease-modifying drug in type 2 diabetes, which reduces the mTORC1 signaling to induce its effects on neuronal plasticity, it was proposed that these mechanisms could also explain the antinociceptive effect of this drug in several models of chronic pain. These studies have highlighted the efficacy of this drug in chronic pain, such as that from neuropathy, insulin resistance, diabetic neuropathy, and fibromyalgia-type pain. Mounting evidence indicates that chronic pain may induce anxiety, depression and cognitive impairment in rodents and humans. Interestingly, metformin is able to reverse some of these consequences of pathological pain in rodents. The purpose of this review was to analyze the current evidence about the effects of metformin in chronic pain and three of its comorbidities (anxiety, depression and cognitive impairment).

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“…Scheen [60] and Graham et al [27] indicated that metformin shows nonlinear pharmacokinetics caused by a reduced bioavailability at higher doses. Moreover, Chung et al [11] revealed that effects on glycaemia did not linearly increase with higher doses of metformin in humans. The results of these studies led to the assumption that a similar phenomenon could have been possible in our study.…”

Section: Discussionmentioning

confidence: 99%

Does the antidiabetic drug metformin affect embryo development and the health of brown trout (Salmo trutta f. fario)?

et al. 2018

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BackgroundDue to the rising number of type 2 diabetes patients, the antidiabetic drug, metformin is currently among those pharmaceuticals with the highest consumption rates worldwide. Via sewage-treatment plants, metformin enters surface waters where it is frequently detected in low concentrations (µg/L). Since possible adverse effects of this substance in aquatic organisms have been insufficiently explored to date, the aim of this study was to investigate the impact of metformin on health and development in brown trout (Salmo trutta f. fario) and its microbiome.ResultsBrown trout embryos were exposed to 0, 1, 10, 100 and 1000 µg/L metformin over a period from 48 days post fertilisation (dpf) until 8 weeks post-yolk sac consumption at 7 °C (156 dpf) and 11 °C (143 dpf). Chemical analyses in tissues of exposed fish showed the concentration-dependent presence of metformin in the larvae. Mortality, embryonic development, body length, liver tissue integrity, stress protein levels and swimming behaviour were not influenced. However, compared to the controls, the amount of hepatic glycogen was higher in larvae exposed to metformin, especially in fish exposed to the lowest metformin concentration of 1 µg/L, which is environmentally relevant. At higher metformin concentrations, the glycogen content in the liver showed a high variability, especially for larvae exposed to 1000 µg/L metformin. Furthermore, the body weight of fish exposed to 10 and 100 µg/L metformin at 7 °C and to 1 µg/L metformin at 11 °C was decreased compared with the respective controls. The results of the microbiome analyses indicated a shift in the bacteria distribution in fish exposed to 1 and 10 µg/L metformin at 7 °C and to 100 µg/L metformin at 11 °C, leading to an increase of Proteobacteria and a reduction of Firmicutes and Actinobacteria.ConclusionsOverall, weight reduction and the increased glycogen content belong to the described pharmaceutical effects of the drug in humans, but this study showed that they also occur in brown trout larvae. The impact of a shift in the intestinal microbiome caused by metformin on the immune system and vitality of the host organism should be the subject of further research before assessing the environmental relevance of the pharmaceutical.Electronic supplementary materialThe online version of this article (10.1186/s12302-018-0179-4) contains supplementary material, which is available to authorized users.

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A non-linear pharmacokinetic-pharmacodynamic relationship of metformin in healthy volunteers: An open-label, parallel group, randomized clinical study

Cited by 20 publications

References 26 publications

Mechanisms of action of metformin with special reference to cardiovascular protection

Mechanisms of action of metformin with special reference to cardiovascular protection

Metformin: A Prospective Alternative for the Treatment of Chronic Pain

Does the antidiabetic drug metformin affect embryo development and the health of brown trout (Salmo trutta f. fario)?

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