Defective Hydroxylation of Phenformin as a Determinant of Drug Toxicity

Bosisio, E.; Kienle, Marzia Galli; Galli, Giovanni; Ciconali, M; Negri, Alberto; Sessa, A.; Morosati, S; Sirtori, Cesare R.

doi:10.2337/diab.30.8.644

Cited by 10 publications

(9 citation statements)

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“…Phenformin was withdrawn from the market in the late 1990 s for inducing fatal lactic acidosis, mainly related to the different ability of the subjects to metabolize the drug in the liver. In subjects with low metabolic capacity, accumulation of the drug and toxic levels occurred leading to potential fatal lactic acidosis [ 15 , 16 ]. As shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

Metformin, chronic nephropathy and lactic acidosis: a multi-faceted issue for the nephrologist

Mariano

Biancone

2020

J Nephrol

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Metformin is currently considered a first-line therapy in type 2 diabetic patients. After issuing warnings for decades about the risks of lactic acidosis in patients with chronic nephropathy, metformin is now being re-evaluated. The most recent evidence from the literature has demonstrated both a low, acceptable risk of lactic acidosis and a series of favorable effects, which go beyond its hypoglycemic activity. Patients treated with metformin show a significant mortality reduction and lower progression towards end-stage renal disease in comparison with those treated with other hypoglycemic drugs. Concerning lactic acidosis, in the last few years it has been shown how lactic acidosis almost always developed when patients kept taking the drug in the face of a concomitant disease or situation such as sepsis, fever, diarrhea, vomiting, which reduced metformin renal clearance. Actually, clearance of metformin is mainly renal, both by glomerular filtration and tubular secretion (apparent clearance 933–1317 ml/min, half-life < 3 h). As regards treatment, in cases of lactic acidosis complicated by acute kidney injury, continuous renal replacement therapy (CRRT) plays a crucial role. Besides the elimination of metformin, CRRT improves survival by correcting acidosis, electrolyte alterations, and maintaining fluid balance. Lactic acidosis almost always develops because of preventable drug accumulation. Therefore, prevention is a key factor. Patients should be aware that discontinuation for a limited time does not affect their health, even when it may be inappropriate, but it may avoid a serious, potentially fatal adverse event.

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Section: Introductionmentioning

confidence: 99%

Metformin, chronic nephropathy and lactic acidosis: a multi-faceted issue for the nephrologist

Mariano

Biancone

2020

J Nephrol

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“…Ironically, soon after withdrawal of phenformin it was noted that about 9% of Europids have a mutation in the CYP2D6 gene, encoding the cytochrome P450 2D6 (CYP2D6) hydroxylation enzyme, causing a build-up of unmetabolised phenformin, leading to lactic acidosis [52,53]: a problem that modern pharmacogenomics could deal with.…”

Section: Lactic Acidosismentioning

confidence: 99%

Metformin: historical overview

2017

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Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega officinalis (also known as goat's rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Guanidine derivatives, including metformin, were synthesised and some (not metformin) were used to treat diabetes in the 1920s and 1930s but were discontinued due to toxicity and the increased availability of insulin. Metformin was rediscovered in the search for antimalarial agents in the 1940s and, during clinical tests, proved useful to treat influenza when it sometimes lowered blood glucose. This property was pursued by the French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. However, metformin received limited attention as it was less potent than other glucose-lowering biguanides (phenformin and buformin), which were generally discontinued in the late 1970s due to high risk of lactic acidosis. Metformin's future was precarious, its reputation tarnished by association with other biguanides despite evident differences. The ability of metformin to counter insulin resistance and address adult-onset hyperglycaemia without weight gain or increased risk of hypoglycaemia gradually gathered credence in Europe, and after intensive scrutiny metformin was introduced into the USA in 1995. Long-term cardiovascular benefits of metformin were identified by the UK Prospective Diabetes Study (UKPDS) in 1998, providing a new rationale to adopt metformin as initial therapy to manage hyperglycaemia in type 2 diabetes. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications.

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“…Third, alterations of the enzymes that metabolize phenformin (CYP2D6 and P-glycoprotein) can modulate phenformin circulating levels and consequentially the risk of lactic acidosis. Indeed, it has been demonstrated that patients that are poor CYP2D6 metabolizers show higher levels of phenformin plasma concentrations that lead to higher toxicity [59]. The risk of lactic acidosis is also increased by CYP2D6 gene mutations that lead to high levels of unmetabolized phenformin [1,59].…”

Section: Phenformin: Uptake Therapeutic Concentration Excretionmentioning

confidence: 99%

“…Indeed, it has been demonstrated that patients that are poor CYP2D6 metabolizers show higher levels of phenformin plasma concentrations that lead to higher toxicity [59]. The risk of lactic acidosis is also increased by CYP2D6 gene mutations that lead to high levels of unmetabolized phenformin [1,59].…”

Section: Phenformin: Uptake Therapeutic Concentration Excretionmentioning

confidence: 99%

The Mechanism of Action of Biguanides: New Answers to a Complex Question

Magno

Pastena

Bordone

et al. 2022

Cancers

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Biguanides are a family of antidiabetic drugs with documented anticancer properties in preclinical and clinical settings. Despite intensive investigation, how they exert their therapeutic effects is still debated. Many studies support the hypothesis that biguanides inhibit mitochondrial complex I, inducing energy stress and activating compensatory responses mediated by energy sensors. However, a major concern related to this “complex” model is that the therapeutic concentrations of biguanides found in the blood and tissues are much lower than the doses required to inhibit complex I, suggesting the involvement of additional mechanisms. This comprehensive review illustrates the current knowledge of pharmacokinetics, receptors, sensors, intracellular alterations, and the mechanism of action of biguanides in diabetes and cancer. The conditions of usage and variables affecting the response to these drugs, the effect on the immune system and microbiota, as well as the results from the most relevant clinical trials in cancer are also discussed.

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Defective Hydroxylation of Phenformin as a Determinant of Drug Toxicity

Cited by 10 publications

References 0 publications

Metformin, chronic nephropathy and lactic acidosis: a multi-faceted issue for the nephrologist

Metformin, chronic nephropathy and lactic acidosis: a multi-faceted issue for the nephrologist

Metformin: historical overview

The Mechanism of Action of Biguanides: New Answers to a Complex Question

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