772
Views
2
CrossRef citations to date
0
Altmetric
Review

Metformin transporter pharmacogenomics: insights into drug disposition—where are we now?

, , ORCID Icon, &
Pages 1149-1159 | Received 25 Jun 2018, Accepted 25 Oct 2018, Published online: 13 Nov 2018

References

  • Cho NH, Shaw JE, Karuranga S, et al. IDF diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–281.
  • American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care. 2018;41:S73–S85.
  • Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364–1379.
  • Rodbard HW, Jellinger PS. The American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) algorithm for managing glycaemia in patients with type 2 diabetes mellitus: comparison with the ADA/EASD algorithm. Diabetologia. 2010;53:2458–2460.
  • Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the diabetes prevention program outcomes study. Diabetes Care. 2012;35:731–737.
  • Pedersen AJT, Stage TB, Glintborg D, et al. The pharmacogenetics of metformin in women with polycystic ovary syndrome: a randomized trial. Basic Clin Pharmacol Toxicol. 2018;122:239–244.
  • Joo M, Park J, Chun H. Additional benefits of routine drugs on gastrointestinal cancer: statins, metformin, and proton pump inhibitors. Dig Dis. 2018;36:1–14.
  • Pernicova I, Korbonits M. Metformin–mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10:143–156.
  • Witters LA. The blooming of the French lilac. J Clin Invest. 2001;108:1105–1107.
  • Lalau JD. Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf. 2010;33:727–740.
  • Liang X, Giacomini KM. Transporters involved in metformin pharmacokinetics and treatment response. J Pharm Sci. 2017;106:2245–2250.
  • Sahin M, Tutuncu NB, Ertugrul D, et al. Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus. J Diabetes Complicat. 2007;21:118–123.
  • Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316:823–828.
  • Florez JC. The pharmacogenetics of metformin. Diabetologia. 2017;60:1648–1655.
  • Pawlyk AC, Giacomini KM, McKeon C, et al. Metformin pharmacogenomics: current status and future directions. Diabetes. 2014;63:2590–2599.
  • Pearson ER. Personalized medicine in diabetes: the role of ‘omics’ and biomarkers. Diabet Med. 2016;33:712–717.
  • Todd JN, Florez JC. An update on the pharmacogenomics of metformin: progress, problems and potential. Pharmacogenomics. 2014;15:529–539.
  • Srinivasan S, Yee SW, Giacomini KM. Pharmacogenetics of antidiabetic drugs. Adv Pharmacol. 2018;83:361–389.
  • Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50:81–98.
  • Kimura N, Okuda M, Inui K. Metformin transport by renal basolateral organic cation transporter hOCT2. Pharm Res. 2005;22:255–259.
  • Masuda S, Terada T, Yonezawa A, et al. Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J Am Soc Nephrol. 2006;17:2127–2135.
  • Christensen MM, Brasch-Andersen C, Green H, et al. The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenet Genom. 2011;21:837–850.
  • Robert F, Fendri S, Hary L, et al. Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects. Diabetes Metab. 2003;29:279–283.
  • Wu CY, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22:11–23.
  • Liang X, Chien HC, Yee SW, et al. Metformin is a substrate and inhibitor of the human thiamine transporter, THTR-2 (SLC19A3). Mol Pharm. 2015;12:4301–4310.
  • Takane H, Shikata E, Otsubo K, et al. Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics. 2008;9:415–422.
  • Rask-Andersen M, Masuram S, Fredriksson R, et al. Solute carriers as drug targets: current use, clinical trials and prospective. Mol Aspects Med. 2013;34:702–710.
  • Motohashi H, Inui K. Multidrug and toxin extrusion family SLC47: physiological, pharmacokinetic and toxicokinetic importance of MATE1 and MATE2-K. Mol Aspects Med. 2013;34:661–668.
  • Koepsell H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med. 2013;34:413–435.
  • Maeda K, Sugiyama Y. Transporter biology in drug approval: regulatory aspects. Mol Aspects Med. 2013;34:711–718.
  • Zhou M, Xia L, Wang J. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos. 2007;35:1956–1962.
  • Nakamichi N, Shima H, Asano S, et al. Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin. J Pharm Sci. 2013;102:3407–3417.
  • Han TK, Proctor WR, Costales CL, et al. Four cation-selective transporters contribute to apical uptake and accumulation of metformin in Caco-2 cell monolayers. J Pharmacol Exp Ther. 2015;352:519–528.
  • Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–1174.
  • Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310:1642–1646.
  • Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348(Pt 3):607–614.
  • Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2017;19:121.
  • Foretz M, Hebrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120:2355–2369.
  • Jablonski KA, McAteer JB, de Bakker PI, et al. Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program. Diabetes. 2010;59:2672–2681.
  • Miller RA, Chu Q, Xie J, et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494:256–260.
  • Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510:542–546.
  • Wu L, Zhou B, Oshiro-Rapley N, et al. An ancient, unified mechanism for metformin growth inhibition in C. Elegans Cancer Cell. 2016;167:1705–18 e13.
  • Nies AT, Koepsell H, Damme K, et al. Organic Cation Transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. In: Fromm MF, Kim RBeditors. Drug Transporters. Berlin, Heidelberg: Springer Berlin Heidelberg; 2011. p. 105–167.
  • Koepsell H, Lips K, Volk C. Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res. 2007;24:1227–1251.
  • Nies AT, Koepsell H, Winter S, et al. Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology. 2009;50:1227–1240.
  • Nies AT, Schwab M. Organic cation transporter pharmacogenomics and drug-drug interaction. Expert Rev Clin Pharmacol. 2010;3:707–711.
  • PharmGKB. The Pharmacogenomics Knowledgebase. [Cited 2018 Jun 20]. Available from: https://www.pharmgkb.org/.
  • Kerb R, Brinkmann U, Chatskaia N, et al. Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics. 2002;12:591–595.
  • Shu Y, Leabman MK, Feng B, et al. Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci USA. 2003;100:5902–5907.
  • Wang DS, Jonker JW, Kato Y, et al. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002;302:510–515.
  • Kimura N, Masuda S, Tanihara Y, et al. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005;20:379–386.
  • Zhou K, Donnelly LA, Kimber CH, et al. Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study. Diabetes. 2009;58:1434–1439.
  • Shu Y, Sheardown SA, Brown C, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007;117:1422–1431.
  • Shu Y, Brown C, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008;83:273–280.
  • Sundelin E, Gormsen LC, Jensen JB, et al. Genetic polymorphisms in organic cation transporter 1 attenuates hepatic metformin exposure in humans. Clin Pharmacol Ther. 2017;102:841–848.
  • Christensen MM, Hojlund K, Hother-Nielsen O, et al. Steady-state pharmacokinetics of metformin is independent of the OCT1 genotype in healthy volunteers. Eur J Clin Pharmacol. 2015;71:691–697.
  • Christensen MM, Hojlund K, Hother-Nielsen O, et al. Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial. Diabetologia. 2015;58:2494–2502.
  • Becker ML, Visser LE, van Schaik RH, et al. Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus. Pharmacogenom J. 2009;9:242–247.
  • Becker ML, Visser LE, van Schaik RH, et al. Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. Diabetes. 2009;58:745–749.
  • Becker ML, Visser LE, van Schaik RH, et al. Interaction between polymorphisms in the OCT1 and MATE1 transporter and metformin response. Pharmacogenet Genom. 2010;20:38–44.
  • Tkac I, Klimcakova L, Javorsky M, et al. Pharmacogenomic association between a variant in SLC47A1 gene and therapeutic response to metformin in type 2 diabetes. Diabetes Obes Metab. 2013;15:189–191.
  • Dujic T, Zhou K, Yee SW, et al. Variants in pharmacokinetic transporters and glycemic response to metformin: a metgen meta-analysis. Clin Pharmacol Ther. 2017;101:763–772.
  • Zhou Y, Ye W, Wang Y, et al. Genetic variants of OCT1 influence glycemic response to metformin in Han Chinese patients with type-2 diabetes mellitus in Shanghai. Int J Clin Exp Pathol. 2015;8:9533–9542.
  • Dujic T, Zhou K, Donnelly LA, et al. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes. 2015;64:1786–1793.
  • Dujic T, Causevic A, Bego T, et al. Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with type 2 diabetes. Diabet Med. 2016;33:511–514.
  • Wang ZJ, Yin OQ, Tomlinson B, et al. OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine. Pharmacogenet Genom. 2008;18:637–645.
  • Song IS, Shin HJ, Shim EJ, et al. Genetic variants of the organic cation transporter 2 influence the disposition of metformin. Clin Pharmacol Ther. 2008;84:559–562.
  • Chen Y, Li S, Brown C, et al. Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenet Genom. 2009;19:497–504.
  • Christensen MM, Pedersen RS, Stage TB, et al. A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin. Pharmacogenet Genom. 2013;23:526–534.
  • Shikata E, Yamamoto R, Takane H, et al. Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin. J Hum Genet. 2007;52:117–122.
  • Tzvetkov MV, Vormfelde SV, Balen D, et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther. 2009;86:299–306.
  • Tarasova L, Kalnina I, Geldnere K, et al. Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients. Pharmacogenet Genom. 2012;22:659–666.
  • Chen EC, Liang X, Yee SW, et al. Targeted disruption of organic cation transporter 3 attenuates the pharmacologic response to metformin. Mol Pharmacol. 2015;88:75–83.
  • Shirasaka Y, Lee N, Zha W, et al. Involvement of organic cation transporter 3 (Oct3/Slc22a3) in the bioavailability and pharmacokinetics of antidiabetic metformin in mice. Drug Metab Pharmacokinet. 2016;31:385–388.
  • Chen L, Pawlikowski B, Schlessinger A, et al. Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenet Genom. 2010;20:687–699.
  • Lee N, Duan H, Hebert MF, et al. Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands. J Biol Chem. 2014;289:27055–27064.
  • Zaharenko L, Kalnina I, Geldnere K, et al. Single nucleotide polymorphisms in the intergenic region between metformin transporter OCT2 and OCT3 coding genes are associated with short-term response to metformin monotherapy in type 2 diabetes mellitus patients. Eur J Endocrinol. 2016;175:531–540.
  • Nies AT, Damme K, Kruck S, et al. Structure and function of multidrug and toxin extrusion proteins (MATEs) and their relevance to drug therapy and personalized medicine. Arch Toxicol. 2016;90:1555–1584.
  • Ito S, Kusuhara H, Yokochi M, et al. Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney. J Pharmacol Exp Ther. 2012;340:393–403.
  • Hibma JE, Zur AA, Castro RA, et al. The effect of famotidine, a MATE1-selective inhibitor, on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacokinet. 2016;55:711–721.
  • Morrissey KM, Stocker SL, Chen EC, et al. The effect of nizatidine, a MATE2K selective inhibitor, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers. Clin Pharmacokinet. 2016;55:495–506.
  • Chung JY, Cho SK, Kim TH, et al. Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics. Pharmacogenet Genom. 2013;23:365–373.
  • Stocker SL, Morrissey KM, Yee SW, et al. The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther. 2013;93:186–194.
  • Choi JH, Yee SW, Ramirez AH, et al. A common 5ʹ-UTR variant in MATE2-K is associated with poor response to metformin. Clin Pharmacol Ther. 2011;90:674–684.
  • Yoon H, Cho HY, Yoo HD, et al. Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects. Aaps J. 2013;15:571–580.
  • Dujic T, Zhou K, Tavendale R, et al. Effect of serotonin transporter 5-HTTLPR polymorphism on gastrointestinal intolerance to metformin: a GoDARTS study. Diabetes Care. 2016;39:1896–1901.
  • Yee SW, Lin L, Merski M, et al. Prediction and validation of enzyme and transporter off-targets for metformin. J Pharmacokinet Pharmacodyn. 2015;42:463–475.
  • Zhou K, Bellenguez C, Spencer CC, et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet. 2011;43:117–120.
  • van Leeuwen N, Nijpels G, Becker ML, et al. A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts. Diabetologia. 2012;55:1971–1977.
  • Zhou Y, Guo Y, Ye W, et al. RS11212617 is associated with metformin treatment response in type 2 diabetes in Shanghai local Chinese population. Int J Clin Pract. 2014;68:1462–1466.
  • Shokri F, Ghaedi H, Ghafouri Fard S, et al. Impact of ATM and SLC22A1 polymorphisms on therapeutic response to metformin in Iranian diabetic patients. Int J Mol Cell Med. 2016;5:1–7.
  • Florez JC, Jablonski KA, Taylor A, et al. The C allele of ATM rs11212617 does not associate with metformin response in the diabetes prevention program. Diabetes Care. 2012;35:1864–1867.
  • Yee SW, Chen L, Giacomini KM. The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet. 2012;44:359–360.
  • Woods A, Leiper JM, Carling D. The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet. 2012;44:360–361.
  • Zhou K, Yee SW, Seiser EL, et al. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nat Genet. 2016;48:1055–1059.
  • Dawed AY, Ali A, Zhou K, et al. Evidence-based prioritisation and enrichment of genes interacting with metformin in type 2 diabetes. Diabetologia. 2017;60:2231–2239.
  • Stage TB, Lee MP, Hallas J, et al. Early discontinuation of metformin in individuals treated with inhibitors of transporters of metformin. Basic Clin Pharmacol Toxicol. 2016;118:487–495.
  • Stage TB, Brosen K, Christensen MM. A comprehensive review of drug-drug interactions with metformin. Clin Pharmacokinet. 2015;54:811–824.
  • Florez JC. Pharmacogenetics in type 2 diabetes: precision medicine or discovery tool? Diabetologia. 2017;60:800–807.
  • Donnelly LA, Morris AD, Pearson ER. Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study. Diabetes Obes Metab. 2009;11:338–342.
  • Burton JH, Johnson M, Johnson J, et al. Addition of a gastrointestinal microbiome modulator to metformin improves metformin tolerance and fasting glucose levels. J Diabetes Sci Technol. 2015;9:808–814.
  • Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528:262–266.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.