Toxicity and toxicokinetics of metformin in rats

Journal Article · Mon Mar 15 00:00:00 EDT 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.11.026· OSTI ID:21344892

Quaile, Michael P; Melich, David H; Jordan, Holly L; Nold, James B ^[1]; Chism, Jack P; Polli, Joseph W; Smith, Glenn A ^[2]

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1. Safety Assessment, GlaxoSmithKline, 5 Moore Drive, MS: 9-2127, Research Triangle Park, NC 27709-3398 (United States)
2. Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, NC (United States)

Metformin is a first-line drug for the treatment of type 2 diabetes (T2D) and is often prescribed in combination with other drugs to control a patient's blood glucose level and achieve their HbA1c goal. New treatment options for T2D will likely include fixed dose combinations with metformin, which may require preclinical combination toxicology studies. To date, there are few published reports evaluating the toxicity of metformin alone to aid in the design of these studies. Therefore, to understand the toxicity of metformin alone, Crl:CD(SD) rats were administered metformin at 0, 200, 600, 900 or 1200 mg/kg/day by oral gavage for 13 weeks. Administration of >= 900 mg/kg/day resulted in moribundity/mortality and clinical signs of toxicity. Other adverse findings included increased incidence of minimal necrosis with minimal to slight inflammation of the parotid salivary gland for males given 1200 mg/kg/day, body weight loss and clinical signs in rats given >= 600 mg/kg/day. Metformin was also associated with evidence of minimal metabolic acidosis (increased serum lactate and beta-hydroxybutyric acid and decreased serum bicarbonate and urine pH) at doses >= 600 mg/kg/day. There were no significant sex differences in mean AUC{sub 0-24} or C{sub max} nor were there significant differences in mean AUC{sub 0-24} or C{sub max} following repeated dosing compared to a single dose. The no observable adverse effect level (NOAEL) was 200 mg/kg/day (mean AUC{sub 0-24} = 41.1 mug h/mL; mean C{sub max} = 10.3 mug/mL based on gender average week 13 values). These effects should be taken into consideration when assessing potential toxicities of metformin in fixed dose combinations.

• OSTI ID: 21344892
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 243; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ALDEHYDES
ANIMALS
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BLOOD
BODY
BODY FLUIDS
CARBOHYDRATES
CARBOXYLIC ACID SALTS
DOSES
DRUGS
GLANDS
GLUCOSE
HEXOSES
INFLAMMATION
KINETICS
LACTATES
MAMMALS
MATERIALS
MONOSACCHARIDES
NECROSIS
ORGANIC COMPOUNDS
ORGANS
PATHOLOGICAL CHANGES
RATS
RODENTS
SACCHARIDES
SALIVARY GLANDS
SYMPTOMS
TOXICITY
URINE
VERTEBRATES
WASTES