Therapeutic Concentrations of Metformin: A Systematic Review

Kajbaf, F.; Broe, Marc E. De; Lalau, Jean–Daniel

doi:10.1007/s40262-015-0323-x

Cited by 122 publications

(94 citation statements)

References 141 publications

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“…Millimolar concentrations of metformin have also been used previously for studies on the effects of metformin on cultured neurons (24–48 hr, 10 mM [Chau‐Van et al, ]), microglial cells (2 hr with 2–4 mM metformin [Labuzek et al, ]), and peripheral cells (24–72 hr, 1–10 mM [Lee et al, ; Chen et al, ; Smieszek et al, ]). The discrepancy between the experimental concentrations of metformin used in vitro and in vivo and the definition of a reasonable “therapeutic” concentration has been recently discussed in detail (He and Wondisford, ; Kajbaf et al, ). Kajbaf and colleagues () report a wide range of therapeutic plasma concentrations of metformin in the literature.…”

Section: Discussionmentioning

confidence: 99%

“…The discrepancy between the experimental concentrations of metformin used in vitro and in vivo and the definition of a reasonable “therapeutic” concentration has been recently discussed in detail (He and Wondisford, ; Kajbaf et al, ). Kajbaf and colleagues () report a wide range of therapeutic plasma concentrations of metformin in the literature. Furthermore, this study recommends a dose‐efficiency study to measure the plasma metformin concentration that corresponds to the therapeutic metformin concentration (Kajbaf et al, ).…”

Section: Discussionmentioning

confidence: 99%

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The antidiabetic drug metformin decreases mitochondrial respiration and tricarboxylic acid cycle activity in cultured primary rat astrocytes

Hohnholt

Blumrich

Waagepetersen

et al. 2017

J of Neuroscience Research

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Metformin is an antidiabetic drug that is used daily by millions of patients worldwide. Metformin is able to cross the blood-brain barrier and has recently been shown to increase glucose consumption and lactate release in cultured astrocytes. However, potential effects of metformin on mitochondrial tricarboxylic acid (TCA) cycle metabolism in astrocytes are unknown. We investigated this by mapping 13 C labeling in TCA cycle intermediates and corresponding amino acids after incubation of primary rat astrocytes with [U-13 C]glucose. The presence of metformin did not compromise the viability of cultured astrocytes during 4 hr of incubation, but almost doubled cellular glucose consumption and lactate release. Compared with control cells, the presence of metformin dramatically lowered the molecular 13 C carbon labeling (MCL) of the cellular TCA cycle intermediates citrate, a-ketoglutarate, succinate, fumarate, and malate, as well as the MCL of the TCA cycle intermediate-derived amino acids glutamate, glutamine, and aspartate. In addition to the total molecular 13 C labeling, analysis of the individual isotopomers of TCA cycle intermediates confirmed a severe decline in labeling and a significant lowering in TCA cycling ratio in metformin-treated astrocytes. Finally, the oxygen consumption of mitochondria isolated from metformintreated astrocytes was drastically reduced in the presence of complex I substrates, but not of complex II substrates. These data demonstrate that exposure to metformin strongly impairs complex I-mediated mitochondrial respiration in astrocytes, which is likely to cause the observed decrease in labeling of mitochondrial TCA cycle intermediates and the stimulation of glycolytic lactate production. V C 2017 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The antidiabetic drug metformin decreases mitochondrial respiration and tricarboxylic acid cycle activity in cultured primary rat astrocytes

Hohnholt

Blumrich

Waagepetersen

et al. 2017

J of Neuroscience Research

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“…To date, there have been no dose‐efficacy studies measuring corresponding plasma metformin concentrations to blood glucose control. In addition, most of the pharmacokinetic parameters for metformin have been derived from single‐dose studies, rather than steady state concentrations . The question of therapeutic range is further complicated by interindividual variation in plasma metformin concentrations, which is influenced by differences in oral metformin bioavailability, genetic variability in metformin transporters, and renal clearance …”

Section: Pharmacokinetics and Therapeutic Range Of Metforminmentioning

confidence: 99%

Metformin: time to review its role and safety in chronic kidney disease

Tanner

Wang

Liu

et al. 2019

Medical Journal of Australia

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Summary ■Metformin is recommended as first‐line therapy for type 2 diabetes because of its safety, low cost and potential cardiovascular benefits. ■The use of metformin was previously restricted in people with chronic kidney disease (CKD) — a condition that commonly coexists with diabetes — due to concerns over drug accumulation and metformin‐associated lactic acidosis. ■There are limited data from observational studies and small randomised controlled trials to suggest that metformin, independent of its antihyperglycaemic effects, may be associated with lower risk of myocardial infarction, stroke and all‐cause mortality in people with type 2 diabetes and CKD. ■Research into the risk of metformin‐associated lactic acidosis in CKD has previously been limited and conflicting, resulting in significant variation across international guidelines on the safe prescribing and dosing of metformin at different stages of renal impairment. ■Present‐day large scale cohort studies now provide supporting evidence for the safe use of metformin in mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–60 mL/min/1.73m2). However, prescribing metformin in people with severe renal impairment (eGFR < 30 mL/min/1.73m2) remains a controversial issue. Due to observed increased risk of lactic acidosis and all‐cause mortality in people with type 2 diabetes and severe renal impairment, it is generally recommended that metformin is discontinued if renal function falls below this level or during acute renal deterioration.

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“…In the last 50 years, more than 100 publications have performed or discussed metformin pharmacokinetics studies, which Kajbaf et al have listed and discussed in the recent review 18 .…”

Section: Introductionmentioning

confidence: 99%

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

Liang

Giacomini

2017

Journal of Pharmaceutical Sciences

114

101

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Metformin, widely used as first-line treatment for type 2 diabetes, exists primarily as a hydrophilic cation at physiological pHs. As such, membrane transporters play a substantial role in its absorption, tissues distribution, and renal elimination. Multiple organic cation transporters are determinants of the pharmacokinetics of metformin, and many of them are important in its pharmacological action, as mediators of metformin entry into target tissues. Further, a recent genomewide association study (GWAS) in a large multi-ethnic population implicated polymorphisms in SLC2A2, encoding the glucose transporter, GLUT2, as important determinants of response to metformin. Here, we describe the key transporters associated with metformin pharmacokinetics and response.

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Therapeutic Concentrations of Metformin: A Systematic Review

Abstract: Although metformin has been available for over 50 years and it is the key medication in first-line treatment of type 2 diabetes mellitus, major methodological and/or conceptual errors have confounded the literature on its therapeutic concentrations.

Cited by 122 publications

References 141 publications

The antidiabetic drug metformin decreases mitochondrial respiration and tricarboxylic acid cycle activity in cultured primary rat astrocytes

The antidiabetic drug metformin decreases mitochondrial respiration and tricarboxylic acid cycle activity in cultured primary rat astrocytes

Metformin: time to review its role and safety in chronic kidney disease

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

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