title: Toxicity and toxicokinetics of metformin in rats.
abstract: 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 > or =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 > or =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 > or =600 mg/kg/day. There were no significant sex differences in mean AUC(0-24) or C(max) nor were there significant differences in mean AUC(0-24) or C(max) following repeated dosing compared to a single dose. The no observable adverse effect level (NOAEL) was 200 mg/kg/day (mean AUC(0-24)=41.1 microg h/mL; mean C(max)=10.3 microg/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.
authors.affiliation: Safety Assessment, GlaxoSmithKline, 5 Moore Drive, MS: 9-2127, Research Triangle Park, NC 27709-3398, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Quaile
authors.forename: David H
authors.initials: DH
authors.lastname: Melich
authors.forename: Holly L
authors.initials: HL
authors.lastname: Jordan
authors.forename: James B
authors.initials: JB
authors.lastname: Nold
authors.forename: Jack P
authors.initials: JP
authors.lastname: Chism
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Polli
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Smith
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Rhodes
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005123:Eye / Q000187:drug effects; D005260:Female; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D008111:Liver Function Tests; D008297:Male; D013058:Mass Spectrometry; D008687:Metformin / Q000493:pharmacokinetics* / Q000633:toxicity*; D009887:Ophthalmoscopy; D051381:Rats; D012727:Sex Characteristics; D016019:Survival Analysis; D016482:Urinalysis
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin