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The Effect of Nizatidine, a MATE2K Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Volunteers

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Abstract

Background and Objectives

In the proximal tubule, basic drugs are transported from the renal cells to the tubule lumen through the concerted action of the H+/organic cation antiporters, multidrug and toxin extrusion (MATE) 1 and MATE2K. Dual inhibitors of the MATE transporters have been shown to have a clinically relevant effect on the pharmacokinetics of concomitantly administered basic drugs. However, the clinical impact of selective renal organic cation transport inhibition on the pharmacokinetics and pharmacodynamics of basic drugs, such as metformin, is unknown. This study sought to identify a selective MATE2K inhibitor in vitro and to determine its clinical impact on the pharmacokinetics and pharmacodynamics of metformin in healthy subjects.

Methods

Strategic cell-based screening of 71 US Food and Drug Administration (FDA)-approved medications was conducted to identify selective inhibitors of renal organic cation transporters that are capable of inhibiting at clinically relevant concentrations. From this screen, nizatidine was identified and predicted to be a clinically potent and selective inhibitor of MATE2K-mediated transport. The effect of nizatidine on the pharmacokinetics and pharmacodynamics of metformin was evaluated in 12 healthy volunteers in an open-label, randomized, two-phase crossover drug–drug interaction (DDI) study.

Results

In healthy volunteers, the MATE2K-selective inhibitor nizatidine significantly increased the apparent volume of distribution, half-life, and hypoglycemic activity of metformin. However, despite achieving unbound maximum concentrations greater than the in vitro inhibition potency (concentration of drug producing 50 % inhibition [IC50]) of MATE2K-mediated transport, nizatidine did not affect the renal clearance (CLR) or net secretory clearance of metformin.

Conclusion

This study demonstrates that a selective inhibition of MATE2K by nizatidine affected the apparent volume of distribution, tissue concentrations, and peripheral effects of metformin. However, nizatidine did not alter systemic concentrations or the CLR of metformin, suggesting that specific MATE2K inhibition may not be sufficient to cause renal DDIs with metformin.

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References

  1. Somogyi A, Stockley C, Keal J, Rolan P, Bochner F. Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol. 1987;23(5):545–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. Somogyi A, McLean A, Heinzow B. Cimetidine-procainamide pharmacokinetic interaction in man: evidence of competition for tubular secretion of basic drugs. Eur J Clin Pharmacol. 1983;25(3):339–45.

    Article  CAS  PubMed  Google Scholar 

  4. van Crugten J, Bochner F, Keal J, Somogyi A. Selectivity of the cimetidine-induced alterations in the renal handling of organic substrates in humans. Studies with anionic, cationic and zwitterionic drugs. J Pharmacol Exp Ther. 1986;236(2):481–7.

    PubMed  Google Scholar 

  5. Masuda S, Terada T, Yonezawa A, Tanihara Y, Kishimoto K, Katsura T, 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(8):2127–35.

    Article  CAS  PubMed  Google Scholar 

  6. Yokoo S, Yonezawa A, Masuda S, Fukatsu A, Katsura T, Inui K. Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity. Biochem Pharmacol. 2007;74(3):477–87.

    Article  CAS  PubMed  Google Scholar 

  7. Yonezawa A, Masuda S, Yokoo S, Katsura T, Inui K. Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family). J Pharmacol Exp Ther. 2006;319(2):879–86.

    Article  CAS  PubMed  Google Scholar 

  8. Choi JH, Yee SW, Ramirez AH, Morrissey KM, Jang GH, Joski PJ, et al. A common 5’-UTR variant in MATE2-K is associated with poor response to metformin. Clin Pharmacol Ther. 2011;90(5):674–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stocker SL, Morrissey KM, Yee SW, Castro RA, Xu L, Dahlin A, et al. The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther. 2013;93(2):186–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. US FDA. Guidance for industry (draft): drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064982.htm. Accessed May 2013.

  11. European Medicines Agency’s guideline on the investigation of drug interactions. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf. Accessed May 2013.

  12. Hillgren KM, Keppler D, Zur AA, Giacomini KM, Stieger B, Cass CE, et al. Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin Pharmacol Ther. 2013;94(1):52–63.

    Article  CAS  PubMed  Google Scholar 

  13. Bourdet DL, Pritchard JB, Thakker DR. Differential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). J Pharmacol Exp Ther. 2005;315(3):1288–97.

    Article  CAS  PubMed  Google Scholar 

  14. Minematsu T, Iwai M, Umehara K, Usui T, Kamimura H. Characterization of human organic cation transporter 1 (OCT1/SLC22A1)- and OCT2 (SLC22A2)-mediated transport of 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide), a novel small molecule survivin suppressant. Drug Metab Dispos. 2010;38(1):1–4.

    Article  CAS  PubMed  Google Scholar 

  15. Tsuda M, Terada T, Ueba M, Sato T, Masuda S, Katsura T, et al. Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J Pharmacol Exp Ther. 2009;329(1):185–91.

    Article  CAS  PubMed  Google Scholar 

  16. Ito S, Kusuhara H, Kuroiwa Y, Wu C, Moriyama Y, Inoue K, et al. Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine. J Pharmacol Exp Ther. 2010;333(1):341–50.

    Article  CAS  PubMed  Google Scholar 

  17. Tucker GT, Casey C, Phillips PJ, Connor H, Ward JD, Woods HF. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol. 1981;12(2):235–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Goodman LS, Brunton LL, Chabner B, Knollmann BC. Goodman & Gilman’s pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill; 2011.

    Google Scholar 

  19. Moffat AC, Osselton MD, Widdop B, editors. Clarke’s analysis of drugs and poisons: in pharmaceuticals, body fluids and postmortem material. 3rd ed. London: Pharmaceutical Press; 2004.

    Google Scholar 

  20. Zhang S, Lovejoy KS, Shima JE, Lagpacan LL, Shu Y, Lapuk A, et al. Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006;66(17):8847–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen Y, Zhang S, Sorani M, Giacomini KM. Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family. J Pharmacol Exp Ther. 2007;322(2):695–700.

    Article  CAS  PubMed  Google Scholar 

  22. Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007;117(5):1422–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. More SS, Li S, Yee SW, Chen L, Xu Z, Jablons DM, et al. Organic cation transporters modulate the uptake and cytotoxicity of picoplatin, a third-generation platinum analogue. Mol Cancer Ther. 2010;9(4):1058–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kido Y, Matsson P, Giacomini KM. Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. J Med Chem. 2011;54(13):4548–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, et al. Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling. J Med Chem. 2013;56(3):781–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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(10):1956–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008;83(2):273–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen Y, Li S, Brown C, Cheatham S, Castro RA, Leabman MK, et al. Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin. Pharmacogenet Genomics. 2009;19(7):497–504.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Howlett HC, Bailey CJ. A risk-benefit assessment of metformin in type 2 diabetes mellitus. Drug Saf. 1999;20(6):489–503.

    Article  CAS  PubMed  Google Scholar 

  31. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36.

    Article  CAS  PubMed  Google Scholar 

  32. Lau YY, Huang Y, Frassetto L, Benet LZ. effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2007;81(2):194–204.

    Article  CAS  PubMed  Google Scholar 

  33. Abel S, Nichols DJ, Brearley CJ, Eve MD. Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide. Br J Clin Pharmacol. 2000;49(1):64–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Feng B, Obach RS, Burstein AH, Clark DJ, de Morais SM, Faessel HM. Effect of human renal cationic transporter inhibition on the pharmacokinetics of varenicline, a new therapy for smoking cessation: an in vitro-in vivo study. Clin Pharmacol Ther. 2008;83(4):567–76.

    Article  CAS  PubMed  Google Scholar 

  35. Shiga T, Hashiguchi M, Urae A, Kasanuki H, Rikihisa T. Effect of cimetidine and probenecid on pilsicainide renal clearance in humans. Clin Pharmacol Ther. 2000;67(3):222–8.

    Article  CAS  PubMed  Google Scholar 

  36. Somogyi AA, Bochner F, Sallustio BC. Stereoselective inhibition of pindolol renal clearance by cimetidine in humans. Clin Pharmacol Ther. 1992;51(4):379–87.

    Article  CAS  PubMed  Google Scholar 

  37. Pedersen JM, Matsson P, Bergstrom CA, Norinder U, Hoogstraate J, Artursson P. Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2). J Med Chem. 2008;51(11):3275–87.

    Article  CAS  PubMed  Google Scholar 

  38. Vanwert AL, Srimaroeng C, Sweet DH. Organic anion transporter 3 (oat3/slc22a8) interacts with carboxyfluoroquinolones, and deletion increases systemic exposure to ciprofloxacin. Mol Pharmacol. 2008;74(1):122–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kindla J, Muller F, Mieth M, Fromm MF, Konig J. Influence of non-steroidal anti-inflammatory drugs on organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-mediated drug transport. Drug Metab Dispos. 2011;39(6):1047–53.

    Article  CAS  PubMed  Google Scholar 

  40. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, et al. Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012;55(10):4740–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mulgaonkar A, Venitz J, Grundemann D, Sweet DH. Human organic cation transporters 1 (SLC22A1), 2 (SLC22A2), and 3 (SLC22A3) as disposition pathways for fluoroquinolone antimicrobials. Antimicrob Agents Chemother. 2013;57(6):2705–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Busch AE, Karbach U, Miska D, Gorboulev V, Akhoundova A, Volk C, et al. Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol. 1998;54(2):342–52.

    CAS  PubMed  Google Scholar 

  43. Dudley AJ, Bleasby K, Brown CD. The organic cation transporter OCT2 mediates the uptake of beta-adrenoceptor antagonists across the apical membrane of renal LLC-PK1 cell monolayers. Br J Pharmacol. 2000;131(1):71–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Terada T, Masuda S, Asaka J, Tsuda M, Katsura T, Inui K. Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res. 2006;23(8):1696–701.

    Article  CAS  PubMed  Google Scholar 

  45. Tsuda M, Terada T, Asaka J, Ueba M, Katsura T, Inui K. Oppositely directed H + gradient functions as a driving force of rat H+/organic cation antiporter MATE1. Am J Physiol Renal Physiol. 2007;292(2):F593–8.

    Article  CAS  PubMed  Google Scholar 

  46. Chung JY, Cho SK, Kim TH, Kim KH, Jang GH, Kim CO, et al. Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics. Pharmacogenet Genomics. 2013;23(7):365–73.

    Article  CAS  PubMed  Google Scholar 

  47. Dangprapai Y, Wright SH. Interaction of H+ with the extracellular and intracellular aspects of hMATE1. Am J Physiol Renal Physiol. 2011;301(3):F520–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Callaghan JT, Bergstrom RF, Rubin A, Chernish S, Crabtree R, Knadler MP, et al. A pharmacokinetic profile of nizatidine in man. Scand J Gastroenterol Suppl. 1987;136:9–17.

    Article  CAS  PubMed  Google Scholar 

  49. Grover A, Benet LZ. Effects of drug transporters on volume of distribution. AAPS J. 2009;11(2):250–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. FDA. Highlights of prescribing information: nizatidine (Axid). http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/21494s001lbl.pdf. Accessed July 2015.

  51. Stumvoll M, Chintalapudi U, Perriello G, Welle S, Gutierrez O, Gerich J. Uptake and release of glucose by the human kidney. Postabsorptive rates and responses to epinephrine. J Clin Invest. 1995;96(5):2528–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, Kalhan SC. Contributions of gluconeogenesis to glucose production in the fasted state. J Clin Invest. 1996;98(2):378–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stumvoll M, Meyer C, Mitrakou A, Nadkarni V, Gerich JE. Renal glucose production and utilization: new aspects in humans. Diabetologia. 1997;40(7):749–57.

    Article  CAS  PubMed  Google Scholar 

  54. Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab. 2000;2(6):345–50.

    Article  CAS  PubMed  Google Scholar 

  55. Gerich JE. Control of glycaemia. Baillieres Clin Endocrinol Metab. 1993;7(3):551–86.

    Article  CAS  PubMed  Google Scholar 

  56. Woerle HJ, Meyer C, Dostou JM, Gosmanov NR, Islam N, Popa E, et al. Pathways for glucose disposal after meal ingestion in humans. Am J Physiol Endocrinol Metab. 2003;284(4):E716–25.

    Article  CAS  PubMed  Google Scholar 

  57. Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE. Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2012;22(11):820–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 2007;33(1):9–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Toyama K, Yonezawa A, Masuda S, Osawa R, Hosokawa M, Fujimoto S, et al. Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis. Br J Pharmacol. 2012;166(3):1183–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Jennifer Hibma for assistance in preparing the clinical study protocol. We thank Hector Vizoso and all the staff at the General Clinical Research Center (GCRC) at San Francisco General Hospital (SFGH) for their professionalism and enthusiastic assistance in our clinical study. We thank Yong Huang at the UCSF Drugs Services Unit for access to their bioanalytical facilities and Chav Doherty from UCSF SFGH Clinical Laboratory for excellent service.

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Author notes

  1. Kari M. Morrissey

    Present address: Department of Clinical Pharmacology, Genentech, Inc., South San Francisco, CA, USA

  2. Sophie L. Stocker

    Present address: Department of Clinical Pharmacology & Toxicology, St Vincent’s Hospital, Sydney, Australia

  3. Eugene C. Chen

    Present address: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA

Authors and Affiliations

  1. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA

    Kari M. Morrissey, Sophie L. Stocker, Eugene C. Chen, Richard A. Castro & Kathleen M. Giacomini

  2. Department of Anesthesiology, University of California, San Francisco, CA, USA

    Claire M. Brett

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Correspondence to Kathleen M. Giacomini.

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Funding

This project was supported by National Institutes of Health/National Center for Research Resources (NIH/NCRR) University of California, San Francisco (UCSF)-Clinical & Translational Science Institute (CTSI) Grant UL1 RR024131 & NIH Grant GM61390. The authors are solely responsible for the contents and do not necessarily represent the official views of the NIH. This work was also made possible in part by core services provided by the General Clinical Research Center (GCRC) at San Francisco General Hospital (SFGH), funded by the NCRR (NIH MO1-RR00083-44). The authors also acknowledge the following funding sources for SLS. (Allergan) and ECC and KMM (NIH Training Grant T32 GM007175, FDA-CDER/ORISE).

Conflict of interest

The authors have no conflicts of interest that might be relevant to the content of this manuscript.

Ethical approval

The Committee on Human Research at the University of California, San Francisco (Institutional Review Board [IRB] 11-06968) approved the clinical drug–drug interaction study, and all subjects were recruited directly from the Study of Pharmacogenetics in Ethnically Diverse Populations (IRB 10-03167). Informed consent was obtained from all study participants.

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Morrissey, K.M., Stocker, S.L., Chen, E.C. et al. The Effect of Nizatidine, a MATE2K Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Volunteers. Clin Pharmacokinet 55, 495–506 (2016). https://doi.org/10.1007/s40262-015-0332-9

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