Comparison of potential risks of lactic acidosis induction by biguanides in rats

Bando, Kiyoko; Ochiai, Shoko; Kunimatsu, Takeshi; Deguchi, Jiro; Kimura, Juki; Funabashi, Hitoshi; Seki, Takaki

doi:10.1016/j.yrtph.2010.05.005

Cited by 25 publications

(25 citation statements)

References 40 publications

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“…Lactic acidosis is defined as a metabolic acidosis with a pH of less than 7.35 and a lactate concentration greater than 5 mmol/L [15][16][17]. The Cohen-Woods classification system divides lactic acidosis into types A and B.…”

Section: How Does Metformin Lead To the Development Of Lactic Acidosimentioning

confidence: 99%

“…All three have similar mechanisms of action including inhibition of hepatic gluconeogenesis [17]. Biguanides inhibit oxidation of lactate and increase lactate release from skeletal muscle [12].…”

Section: How Does Metformin Lead To the Development Of Lactic Acidosimentioning

confidence: 99%

“…Phenformin is metabolized by CYP2D6 to 4-hydroxyphenformin. A polymorphism has been reported that may cause 5-10 % of Caucasians to have decreased metabolism, contributing to a greater risk of lactic acidosis [17,39].…”

Section: How Does Metformin Lead To the Development Of Lactic Acidosimentioning

confidence: 99%

“…Metformin is less lipophilic and does not demonstrate the same affinity for binding to the mitochondrial membrane. The improved safety profile of metformin may also be related to its shorter half-life, less accumulation within tissues, and renal excretion without the need for hepatic metabolism [17].…”

Section: How Does Metformin Lead To the Development Of Lactic Acidosimentioning

confidence: 99%

“…In 1977, phenformin was withdrawn from the market due to an elevated risk of lactic acidosis and associated mortality [1,16,27]. Prior to withdrawal, the reported incidence of lactic acidosis was 40-64 cases per 100,000 person-years, a 10-20 % higher incidence than metformin [1,16,17,27,40]. It is important to note that many countries outside the USA continue to successfully use phenformin as treatment for NIDDM.…”

Section: How Does Metformin Lead To the Development Of Lactic Acidosimentioning

confidence: 99%

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Metformin-Associated Lactic Acidosis (MALA): Case Files of the Einstein Medical Center Medical Toxicology Fellowship

Kopec

Kowalski

2012

J. Med. Toxicol.

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A 39-year-old man presented to the emergency department after intentionally ingesting 50 tablets of metformin 1,000 mg. The reported time of ingestion was 6 h prior to arrival. Vital signs were: temperature, 37.4°C; pulse, 94 beats per minute; blood pressure, 117/74 mmHg; respirations, 16/min; and oxygen saturation, 96 % on room air. Gastric lavage was performed, and a single dose of activated charcoal was given. His initial serum lactate was 4.3 mmol/L (normal00.67-1.8 mmol/L). The patient had a negative urine drug screen, and acetaminophen and salicylate levels were below detection limits. The patient was admitted for monitoring of lactic acidosis.Twenty hours after arrival, the patient became hypotensive with a blood pressure of 85/45 mmHg. Arterial blood gas analysis revealed a pH of 7.20, pCO 2 19 mmHg, and bicarbonate HCO 3 of 6 mmol/L. A repeat serum lactate at this time was 20 mmol/L, and a basic metabolic panel showed sodium of 134 mmol/L, potassium 3.8 mmol/L, chloride 98 mmol/L, bicarbonate 16 mmol/L, BUN 32 mg/ dL, and creatinine 1.3 mg/dL; the calculated anion gap was 20 mmol/L. A 1-L normal saline bolus was administered, and serum alkalinization was initiated with a sodium bicarbonate drip.

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Section: How Does Metformin Lead To the Development Of Lactic Acidosimentioning

confidence: 99%

Section: How Does Metformin Lead To the Development Of Lactic Acidosimentioning

confidence: 99%

Section: How Does Metformin Lead To the Development Of Lactic Acidosimentioning

confidence: 99%

Section: How Does Metformin Lead To the Development Of Lactic Acidosimentioning

confidence: 99%

Section: How Does Metformin Lead To the Development Of Lactic Acidosimentioning

confidence: 99%

See 3 more Smart Citations

Metformin-Associated Lactic Acidosis (MALA): Case Files of the Einstein Medical Center Medical Toxicology Fellowship

Kopec

Kowalski

2012

J. Med. Toxicol.

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Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS‐010759

Pujalte‐Martin,

Belaïd,

Bost

et al. 2024

Molecular Oncology

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Metformin and IACS‐010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS‐010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS‐01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS‐01075.

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Immunohistochemical localization of OCT2 in the cochlea of various species

Hellberg¹,

Gahm²,

Liu

et al. 2015

The Laryngoscope

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ObjectiveTo locate the organic cation transporter 2 (OCT2) in the cochlea of three different species and to modulate the ototoxicity of cisplatin in the guinea pig by pretreatment with phenformin, having a known affinity for OCT2.Study DesignImmunohistochemical and in vivo study.MethodsSections from the auditory end organs were subjected to immunohistochemical staining in order to identify OCT2 in cochlea from untreated rats, guinea pigs, and a pig. In the in vivo study, guinea pigs were given phenformin intravenously 30 minutes before cisplatin administration. Electrophysiological hearing thresholds were determined, and hair cells loss was assessed 96 hours later. The total amount of platinum in cochlear tissue was determined using mass spectrometry.ResultsOrganic cation transporter 2 was found in the supporting cells and in type I spiral ganglion cells in the cochlea of all species studied. Pretreatment with phenformin did not reduce the ototoxic side effect of cisplatin. Furthermore, the concentration of platinum in the cochlea was not affected by phenformin.ConclusionsThe localization of OCT2 in the supporting cells and type I spiral ganglion cells suggests that this transport protein is not primarily involved in cisplatin uptake from the systemic circulation. We hypothesize that OCT2 transport intensifies cisplatin ototoxicity via transport mechanisms in alternate compartments of the cochlea.Level of EvidenceN/A. Laryngoscope, 125:E320–E325, 2015

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Comparison of potential risks of lactic acidosis induction by biguanides in rats

Cited by 25 publications

References 40 publications

Metformin-Associated Lactic Acidosis (MALA): Case Files of the Einstein Medical Center Medical Toxicology Fellowship

Metformin-Associated Lactic Acidosis (MALA): Case Files of the Einstein Medical Center Medical Toxicology Fellowship

Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS‐010759

Immunohistochemical localization of OCT2 in the cochlea of various species

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