Metformin may interact with the drug such as Iodinated Contrast Materials (ICMs), H2 receptor blockers (Cimetidine, Ranitidine), Proton pump inhibitors, Antimicrobials (Trimethoprim, Cephalexin, Rifampin, Dolutegravir), Ranolazine, Anticancer Drugs (Vandetanib, Imatinib, Nilotinib, Gefitinib, and Erlotinib), Beta adrenergic blockers (Atenolol, Metoprolol).

1. Drug Interactions of
Metformin
Dr P.Naina Mohamed PhD
Pharmacologist

2. Introduction
• Metformin is usually a first-line drug to treat Type 2 diabetes mellitus.
• Metformin is also found to be useful to treat various conditions include…
Prediabetes
Gestational diabetes mellitus (GDM)
Polycystic Ovarian Syndrome (PCOS)
Obesity
Cancer, etc.
• Interaction between one or more coadministered medications leading to
reduced therapeutic efficacy or enhanced toxicity, is termed as “Adverse
drug interaction”.

3. Mechanism of action of
Metformin
Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern
Med. 2002;137(1):25–33.
Metformin
Activation of
AMP-activated
protein kinase
(AMPK)
Decreased hepatic
glucose production
(Inhibition of
gluconeogenesis) and
enhanced glucose
utilization
Reduction of
Blood glucose

4. Metformin Associated Lactic
Acidosis (MALA)
• Most of the adverse drug interactions of Metformin result in
“Metformin Associated Lactic Acidosis (MALA)”.
• The symptoms of MALA include…
Nausea
Vomiting
Fatigue
Lethargy
Confusion
Abdominal pain
Thirst

5. Metformin Associated Lactic
Acidosis (MALA)
• DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: current
perspectives on causes and risk. Metabolism-Clinical and Experimental. 2016 Feb 1;65(2):20-9.
Metformin
Inhibition of
mitochondrial
respiration
Accelerated lactate
production and
reduced lactate
metabolism
Reduction of
Pyruvate
dehydrogenase
activity
Increased
metabolism of
pyruvate to lactate
Decreased
Gluconeogenesis
Decreased
conversion lactate
to glucose

7. Drugs interacting with Metformin
• Metformin may interact with the following drugs…
Iodinated Contrast Materials (ICMs)
H2 receptor blockers (Cimetidine, Ranitidine)
Proton pump inhibitors
Antimicrobials (Trimethoprim, Cephalexin, Rifampin, Dolutegravir)
Ranolazine
Anticancer Drugs (Vandetanib, Imatinib, Nilotinib, Gefitinib, and Erlotinib)
Beta adrenergic blockers (Atenolol, Metoprolol)
Maideen NM, Jumale A, Balasubramaniam R. Drug Interactions of Metformin
Involving Drug Transporter Proteins. Advanced pharmaceutical bulletin. 2017
Dec;7(4):501.

9. Iodinated Contrast Materials (ICMs)
• It is recommended to stop Metformin while using ICM in patients with renal impairment.
Gomez Herrero H, De Arriba Villamor C, Buldain Parra M, Arraiza Sarasa M. Nephrotoxicity due to iodine contrasts
in computerized tomography studies of diabetic outpatients on metformin. An Sist Sanit Navar. 2013;36(2):197–
201.
Metformin +
Iodinated Contrast
Materials (ICMs)
(Angiography,
Urography, etc.)
Contrast-induced
nephropathy (CIN)
Increased risk of
toxic accumulation
of Metformin
Lactic Acidosis

11. Atenolol
Ren J, Zhou Y, Zhang G, Zhou L, Zhao J, Wei Y. et al. Role of age-related decrease of
renal organic cation transporter 2 in the effect of atenolol on renal excretion of
metformin in rats. Eur J Drug Metab Pharmacokinet. 2015;40(3):349–54.
Metformin +
Atenolol
Atenolol reduces
renal blood flow
and inhibits OCT2
Elevated plasma
concentrations of
Metformin
Enhanced risk of
MALA

14. H2 receptor blockers
The malabsorption of vitamin B12 promoted by additive effects of H2 receptor blockers and Metformin and the risk of
vitamin B12 deficiency is increased.
Seo JH, Lee DY, Hong CW, Lee IH, Ahn KS, Kang GW. Severe lactic acidosis and acute pancreatitis associated with
cimetidine in a patient with type 2 diabetes mellitus taking metformin. Intern Med. 2013;52(19):2245–8.
Cho SK, Chung JY. The MATE1 rs2289669 polymorphism affects the renal clearance of metformin following ranitidine
treatment. Int J Clin Pharmacol Ther. 2016;54(4):253–62.
Metformin +
H2 receptor blockers
(Cimetidine &
Ranitidine)
H2 blockers inhibit
Multidrug and Toxin
Extruder 1 (MATE1)
at proximal tubules
Decreased excretion
of Metformin
Elevated plasma
concentrations of
Metformin
Enhanced risk of
MALA

15. Proton Pump Inhibitors
The malabsorption of vitamin B12 promoted by additive effects of Proton pump inhibitors and
Metformin and the risk of vitamin B12 deficiency is increased..
Kim A, Chung I, Yoon SH, Yu KS, Lim KS, Cho JY. et al. Effects of proton pump inhibitors on
metformin pharmacokinetics and pharmacodynamics. Drug Metab Dispos. 2014;42(7):1174–9.
Metformin + Proton
pump inhibitors
(PPIs)
PPIs Inhibit Multidrug
and toxin extruder
(MATE) and OCT2
transporters
Decreased excretion
of Metformin
Elevated plasma
concentrations of
Metformin
Enhanced risk of
MALA

17. Trimethoprim
Grün B, Kiessling MK, Burhenne J, Riedel KD, Weiss J, Rauch G. et al. Trimethoprim-metformin
interaction and its genetic modulation by OCT2 and MATE1 transporters. Br J Clin
Pharmacol. 2013;76(5):787–96.
Metformin +
Trimethoprim
Trimethoprim
inhibits OCTs
and MATEs
Decreased
excretion of
Metformin
Elevated
plasma
concentrations
of Metformin
Enhanced risk
of MALA

19. Cephalexin
Jayasagar G, Krishna Kumar M, Chandrasekhar K, Madhusudan Rao C, Madhusudan Rao Y. Effect
of cephalexin on the pharmacokinetics of metformin in healthy human volunteers. Drug
Metabol Drug Interact. 2002;19(1):41–8.
Metformin +
Cephalexin
Cephalexin
occupies MATE1
Reduced
elimination of
Metformin
Elevated plasma
concentrations
of Metformin
Enhanced risk
of MALA

21. Pyrimethamine
Kusuhara H, Ito S, Kumagai Y, Jiang M, Shiroshita T, Moriyama Y. et al. Effects of a MATE
protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and
at therapeutic dose in healthy subjects. Clin Pharmacol Ther. 2011;89(6):837–44.
Metformin +
Pyrimethamine
Pyrimethamine
inhibits OCT2 and
MATE
transporters
Decreased
excretion of
Metformin
Elevated plasma
concentrations of
Metformin
Enhanced risk of
MALA

23. Vandetanib
Johansson S, Read J, Oliver S, Steinberg M, Li Y, Lisbon E. et al. Pharmacokinetic evaluations
of the co-administrations of vandetanib and metformin, digoxin, midazolam, omeprazole or
ranitidine. Clin Pharmacokinet. 2014;53(9):837–47.
Metformin +
Vandetanib
Vandetanib
inhibits MATE1
and MATE2K
transporters
Reduced
elimination of
Metformin
Elevated
plasma
concentrations
of Metformin
Enhanced risk
of MALA

25. Tyrosine Kinase Inhibitors
• Tyrosine kinase inhibitors such as Imatinib, Nilotinib, Gefitinib, and Erlotinib may reduce the
elimination of Metformin by inhibiting OCTs and MATEs transporters, at clinically relevant
concentrations.43
Minematsu T, Giacomini KM. Interactions of tyrosine kinase inhibitors with organic cation
transporters and multidrug and toxic compound extrusion proteins. Mol Cancer
Ther. 2011;10(3):531–9.
Metformin +
Tyrosine kinase
inhibitors
(Imatinib,
Nilotinib,
Gefitinib, and
Erlotinib)
Inhibition of
OCTs and
MATEs
transporters
Decreased
excretion of
Metformin
Elevated
plasma
concentrations
of Metformin
Enhanced risk
of MALA

26. Conclusion
• Drug interactions can result in significant morbidity and mortality and thus
minimizing the risk for drug interactions should be a goal in drug therapy.
• The risk of adverse effects could be reduced by healthcare professionals through the
screening, education, and follow up on suspected drug interactions.
• The diabetics should always consult their physician and pharmacist.
• The diabetics should bring a list of all of the drugs they are taking (or simply bring
the drugs themselves), including prescription drugs, over-the-counter drugs, and any
supplements, herbal or otherwise, during their visit to the doctor or pharmacist.
• They are encouraged to ask their doctor or pharmacist to look over their list for any
potentially dangerous combinations.
• It is recommended that people fill all their prescriptions at one pharmacy, if
possible.

27. References
• Stockley’s Drug Interactions, 9e
Karen Baxter
• British National Formulary
June 2013
• Basic & Clinical Pharmacology, 12e
Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor
• Goodman & Gilman's The Pharmacological Basis of Therapeutics,
12e
Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann

28. References
• Maideen NM, Jumale A, Balasubramaniam R. Drug Interactions of Metformin
Involving Drug Transporter Proteins. Advanced pharmaceutical bulletin. 2017
Dec;7(4):501.
• Triplitt C. Drug interactions of medications commonly used in diabetes.
Diabetes Spectrum. 2006 Oct 1;19(4):202-11.
• Scheen AJ. Clinical pharmacokinetics of metformin. Clinical
pharmacokinetics. 1996 May 1;30(5):359-71.
• Müller F, Fromm MF. Transporter-mediated drug–drug interactions.
Pharmacogenomics. 2011 Jul;12(7):1017-37.
• Kimura N, Okuda M, Inui KI. Metformin transport by renal basolateral organic
cation transporter hOCT2. Pharmaceutical research. 2005 Feb 1;22(2):255-9.

29. References
• Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong J, Furlong TJ,
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• Tornio A, Niemi M, Neuvonen PJ, Backman JT. Drug interactions with oral
antidiabetic agents: pharmacokinetic mechanisms and clinical implications.
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• Zhang L, Zhang YD, Zhao P, Huang SM. Predicting drug–drug interactions: an
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