Drug interactions of Metformin

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. 

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.

6. Drugs interacting with Metformin Metformin may interact with the following drugs… Iodinated Contrast Materials ( ICMs) H 2  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.

7. 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.

8. 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.

9. H 2  receptor blockers The malabsorption of vitamin B12 promoted by additive effects of H 2  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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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

18. 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.

19. References Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong J, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE. Clinical pharmacokinetics of metformin. Clinical pharmacokinetics. 2011 Feb 1;50(2):81-98 . Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE. Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenetics and genomics. 2012 Nov;22(11):820 . Tornio A, Niemi M, Neuvonen PJ, Backman JT. Drug interactions with oral antidiabetic agents: pharmacokinetic mechanisms and clinical implications. Trends in pharmacological sciences. 2012 Jun 1;33(6):312-22 . Zhang L, Zhang YD, Zhao P, Huang SM. Predicting drug–drug interactions: an FDA perspective. The AAPS journal. 2009 Jun 1;11(2):300-6.