Metformin (1,1-dimethylbiguanide) is a biguanide primarily used for the management of non–insulin-dependent diabetes mellitus in humans and is the recommended first-line treatment following diagnosis.1 Metformin does not appear to affect pancreatic beta cell production of insulin, but to be effective, it requires the presence of circulating insulin.2,3 Metformin reduces blood glucose concentration by enhancing muscle cell sensitivity to insulin and therefore increases muscle glucose metabolism.3–7 Metformin also decreases hepatic gluconeogenesis and glycogenolysis. The overall consequence of these actions is to lower blood glucose concentrations without causing hypoglycemia.
There is clinical evidence that humans receiving metformin for treatment of non–insulin-dependent diabetes mellitus have a reduced lifetime incidence of cancer.8,9 This finding has led to substantial research to better understand metformin's activity, including attempts to define the precise molecular target of metformin. Metformin's mechanism of action is not understood but appears to target the enzyme AMPK. Increased activity of AMPK enhances glucose uptake from the blood into muscles.8,10 The upstream regulator of AMPK is a protein kinase known as liver kinase B1, which is a tumor suppressor. Furthermore, results of in vitro investigations11 suggest that metformin may inhibit the proliferation of MDR cell lines and decrease the expression of the MDR marker, MDR1 (p-glycoprotein), leading to reversal of chemotherapy resistance. This may be related to decreased expression of the drug efflux transporters (eg, MDR1), given that these efflux transporters may be responsible for reduced effectiveness of chemotherapy agents such as doxorubicin.11 A further possible explanation of the mechanism is related to the impact of metformin on chronic inflammation. Adenosine monophosphate–activated protein kinase may have the capacity to reduce inflammation, which is an important component of the development and progression of cancer.10
A dearth of information exists regarding the ideal therapeutic concentration of metformin in humans. Kajbaf et al12 performed a systematic review of the human medical literature and found reported therapeutic values ranged widely from 0.129 to 90 mg/L (with boundary values of 0 to 1,800 mg/L). Detailed assessment of the available data suggests that a serum metformin concentration of 2.5 mg/L is the likely upper limit of the therapeutic range, whereas a lower limit could not be determined.12
To the authors’ knowledge, complete reports of metformin pharmacokinetic or pharmacodynamic data from which to determine an appropriate dose regimen in dogs are lacking. A recent publication13 reported the development and validation of a high-performance liquid chromatography–tandem spectrometry method for the simultaneous determination of plasma concentrations of metformin and pioglitazone (another orally administered anti-diabetic agent) in 6 Beagles.
The use of metformin in other species has provided basic knowledge of the drug's pharmacokinetics. Metformin is excreted unchanged in urine in humans and cats.1,4,5,14 As such, normal kidney function is imperative for the excretion of this drug and to prevent its accumulation. In humans, lactic acidosis is a rare life-threatening condition that has been linked to high circulating metformin concentrations and is often associated with renal dysfunction.4–6 In dogs, the adverse effects of metformin, of which vomiting is most common, have been documented only after accidental oral ingestion of large amounts of the drug; even at high doses, these adverse effects are minimal.14
Given the potential benefits of metformin indicated by results of recent human studies,2,8,9,15 determination of the pharmacokinetics of metformin in dogs will allow for further investigation into its potential use in cancer prevention and treatment for both companion animals and humans. The purpose of the study reported here was to investigate the pharmacokinetics of metformin in healthy dogs after IV and oral bolus administrations and determine the oral dose of metformin that yields serum concentrations equivalent to those thought to be effective in humans.
Supported by funding provided by the Western College of Veterinary Medicine Companion Animal Health Fund.
Presented in abstract form at the American College of Veterinary Internal Medicine Forum, Indianapolis, June 2015.
Adenosine monophosphate–activated protein kinase
Area under the serum concentration–time curve
Flow injection analysis–tandem mass spectrometry
Glomerular filtration rate
Organic cation transporter
Time to maximum serum concentration
Volume of distribution
Metformin-HCl, Sigma Chemical Co, St Louis, Mo.
Metformin-HCl tablets, 500 mg, Valeant, Laval, QC, Canada.
Indwelling jugular double-lumen sampling catheter, 7F × 20 cm, MILA International Inc, Florence, Ky.
Sorvall ST 8 benchtop centrifuge, ThermoFisher Scientific, Burlington, ON, Canada.
Allegra 25R centrifuge, Beckman, Indianapolis, Ind.
GraphPad Prism 5.0, GraphPad Software Inc, San Diego, Calif.
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