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Pharmacokinetic Interaction Between Imatinib and Metformin in Rats

  • Original Research Article
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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Imatinib is primarily transported into the liver by organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B3 (OATP1B3), and novel organic cation transporter 2 (OCTN2), which is the first step in the metabolic and elimination of imatinib. Patients taking imatinib may concurrently take metformin, a substrate for OCT1. Drug-drug interactions (DDI) may occur between imatinib and metformin, affecting the clinical efficacy of imatinib. This experiment aimed to investigate the pharmacokinetic effects of metformin on imatinib and its active metabolism of N-desmethyl imatinib in rats.

Methods

Twenty healthy Sprague-Dawley rats were selected and randomly divided into control and experimental groups (10 rats per group). The control group was orally administered imatinib (30 mg/kg) for 14 days, and the experimental group was orally co-administered imatinib (30 mg/kg) and metformin (200 mg/kg) for 14 days. The plasma concentrations of imatinib and N-desmethyl imatinib in rats were determined by ultra-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by DAS2.0 software.

Results

After single-dose co-administration of imatinib and metformin on day 1, the AUC0−24 (area under the plasma concentration-time curve) and Cmax (maximum concentration) of imatinib and the MRT (mean residence time) and Cmax of N-desmethyl imatinib in the experimental group were significantly decreased compared with the control group (P < 0.05). After multiple-dose co-administration of imatinib and metformin for 14 days, the AUC0−24 and Cmax of both imatinib and N-desmethyl imatinib were significantly decreased in the experimental group (P < 0.05).

Conclusion

With both single and multiple co-administration doses, metformin significantly changed the pharmacokinetic parameters of imatinib and N-desmethyl imatinib. The results suggest that care should be taken when metformin and imatinib are co-administered.

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Code Availability

Not applicable.

Data Availability

The datasets generated and analyzed during the current study are not publicly available but are available from the corresponding author.

References

  1. Belda-Iniesta C, Pernia O, Simo R. Metformin: a new option in cancer treatment. Clin Transl Oncol. 2011;13(6):363–7.

    Article  CAS  PubMed  Google Scholar 

  2. Viollet B, Guigas B, Garcia NS, Leclerc J, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci. 2012;122(6):253–70.

    Article  CAS  Google Scholar 

  3. Zamek-Gliszczynski MJ, Bao JQ, Day JS, Higgins JW. Metformin sinusoidal efflux from the liver is consistent with negligible biliary excretion and absence of enterohepatic cycling. Drug Metab Dispos. 2013;41(11):1967–71.

    Article  CAS  PubMed  Google Scholar 

  4. Audia P, Feinfeld DA, Dubrow A, Winchester JF. Metformin-induced lactic acidosis and acute pancreatitis precipitated by diuretic, celecoxib, and candesartan-associated acute kidney dysfunction. Clin Toxicol. 2008;46(2):164–6.

    Article  CAS  Google Scholar 

  5. Ding Y, Jia Y, Song Y, Lu C, Li Y, Chen M, et al. The effect of lansoprazole, an OCT inhibitor, on metformin pharmacokinetics in healthy subjects. Eur J Clin Pharmacol. 2014;70(2):141–6.

    Article  CAS  PubMed  Google Scholar 

  6. White DL, Saunders VA, Dang P, Engler J, Zannettino AC, Cambareri AC, et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood. 2006;108(2):697–704.

    Article  CAS  PubMed  Google Scholar 

  7. Widmer N, Bardin C, Chatelut E, Paci A, Beijnen J, Levêque D, et al. Review of therapeutic drug monitoring of anticancer drugs part two—targeted therapies. Eur J Cancer. 2014;50(12):2020–36.

    Article  CAS  PubMed  Google Scholar 

  8. Maher HM, Alzoman NZ, Shehata SM. Ultra-performance LC–MS/MS study of the pharmacokinetic interaction of imatinib with selected vitamin preparations in rats. Bioanalysis. 2018;10(14):1099–113.

    Article  CAS  PubMed  Google Scholar 

  9. Alzoman NZ, Maher HM, Shehata SM, Abanmy NO. UPLC–MS/MS study of the effect of dandelion root extract on the plasma levels of the selected irreversible tyrosine kinase inhibitors dasatinib, imatinib and nilotinib in rats: potential risk of pharmacokinetic interactions. Biomed Chromatogr. 2019;33(12): e4674.

    Article  CAS  PubMed  Google Scholar 

  10. Hemminki K, Li X, Sundquist J, Sundquist K. Risk of cancer following hospitalization for type 2 diabetes. Oncologist. 2010;15(6):548–55.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Darweesh RS, El-Elimat T, Zayed A, Khamis TN, Sharie AHA. The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats. BMC Pharmacol Toxicol. 2020;21(1):77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Novakovic ZM, Leinung MC, Grasso P. [D-Leu-4]-OB3, an orally bioavailable leptin-related synthetic peptide insulin sensitizer: a study comparing the efficacies of [D-Leu-4]-OB3 and metformin on energy balance and glycemic regulation in insulin-deficient male Swiss Webster mice. Peptides. 2013;43(1):167–73.

    Article  CAS  PubMed  Google Scholar 

  13. Chen X, Du L, Liu M. Development, validation, and application of an UPLC-MS/MS method for vancomycin, norvancomycin, methotrexate, paclitaxel, and imatinib analysis in human plasma. Ann Clin Biochem. 2022;59(4):253–63.

    Article  CAS  PubMed  Google Scholar 

  14. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM). Bioanalytical Method Validation Guidance for Industry. 2018. Available at https://www.fda.gov/media/70858/download. Accessed 8 October 2023.

  15. Zhong DF, Li G, Liu CX. Guidance on bioanalysis: method validation and analysis of study samples (Draft). Drug Evaluat Res. 2011;34(6):409–15.

    Google Scholar 

  16. Karbownik A, Szkutnik-Fiedler D, Czyrski A, Kostewicz N, Kaczmarska P, Bekier M, et al. Pharmacokinetic Interaction between sorafenib and atorvastatin, and sorafenib and metformin in Rats. Pharmaceutics. 2020;12(7):600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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 

  18. Skoglund K, Boiso Moreno S, Jönsson J-I, Vikingsson S, Carlsson B, Gréen H. Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line. Pharmacogenet Genom. 2014;24(1):52–61.

    Article  CAS  Google Scholar 

  19. Eechoute K, Sparreboom A, Burger H, Franke RM, Schiavon G, Verweij J, et al. Drug transporters and imatinib treatment: implications for clinical practice. Clin Cancer Res. 2011;17(3):406–15.

    Article  CAS  PubMed  Google Scholar 

  20. Hu S, Franke RM, Filipski KK, Hu C, Orwick SJ, De Bruijn EA, et al. Interaction of imatinib with human organic ion carriers. Clin Cancer Res. 2008;14(10):3141–8.

    Article  CAS  PubMed  Google Scholar 

  21. Jensen JB, Sundelin EI, Jakobsen S, Gormsen LC, Munk OL, Frøkiær J, et al. [11C]-Labeled metformin distribution in the liver and small intestine using dynamic positron emission tomography in mice demonstrates tissue-specific transporter dependency. Diabetes. 2016;65(6):1724–30.

    Article  CAS  PubMed  Google Scholar 

  22. Han T, Proctor WR, Costales CL, Cai H, Everett RS, Thakker DR. Four cation-selective transporters contribute to apical uptake and accumulation of metformin in caco-2 cell monolayers. J Pharmacol Exp Ther. 2015;352(3):519–28.

    Article  PubMed  Google Scholar 

  23. Noritaka N, Shima H, Satoshi A, Ishimoto T, Sugiura T, Matsubara K, et al. Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin. J Pharm Sci. 2013;102(9):3407–17.

    Article  Google Scholar 

  24. Umehara KI, Iwatsubo T, Noguchi K, Kamimura H. Functional involvement of organic cation transporter1 (OCT1/Oct1) in the hepatic uptake of organic cations in humans and rats. Xenobiotica. 2007;37(8):818–31.

    Article  CAS  PubMed  Google Scholar 

  25. Drozdzik M, Busch D, Lapczuk J, Müller J, Ostrowski M, Kurzawski M, et al. Protein abundance of clinically relevant drug transporters in the human liver and intestine: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther. 2019;105(5):1204–12.

    Article  CAS  PubMed  Google Scholar 

  26. Muller J, Keiser M, Drozdzik M, Oswald S. Expression, regulation and function of intestinal drug transporters: an update. Biol Chem. 2017;398(2):175–92.

    Article  PubMed  Google Scholar 

  27. Jin S, Lee S, Jeon JH, Kim H, Choi MK, Song IS. Enhanced intestinal permeability and plasma concentration of metformin in rats by the repeated administration of red ginseng extract. Pharmaceutics. 2019;11(4):189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Frank S, Binder L, Hafke A, Brandhorst G, Braulke F, Haase D, et al. Use of total and unbound imatinib and metabolite LC-MS/MS assay to understand individual responses in CML and GIST patients. Ther Drug Monit. 2011;33(5):632–43.

    Article  Google Scholar 

  29. van Erp NP, Gelderblom H, Karlsson MO, Li J, Zhao M, Ouwerkerk J, et al. Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. Clin Cancer Res. 2007;13(24):7394–400.

    Article  PubMed  Google Scholar 

  30. Delbaldo C, Chatelut E, Ré M, Deroussent A, Séronie-Vivien S, Jambu A, et al. Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors. Clin Cancer Res. 2006;12(20):6073–8.

    Article  CAS  PubMed  Google Scholar 

  31. Wieczorek A, Uharek L. Management of chronic myeloid leukemia patients resistant to tyrosine kinase inhibitors treatment. Biomarker Insights. 2016;10(3):49–54.

    PubMed  PubMed Central  Google Scholar 

  32. Obbergh FV, Knoops L, Devos T, Beguin Y, Graux C, Benghiat F, et al. The clinical relevance of imatinib plasma trough concentrations in chronic myeloid leukemia. A Belgian study. Clin Biochem. 2017;50(7):452–4.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors acknowledge the support from the Fourth Hospital of Hebei Medical University (Shijiazhuang, China). The authors also acknowledge the support from People's Livelihood Science and Technology special projects of Key Research and Development Plan of the Science and Technology Department of Hebei Province (program number: 20377757D). The fund sponsor did not participate in the design and research of the article.

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Authors and Affiliations

  1. Department of Pharmacy, The Fourth Hospital of Hebei Medical University, Hebei Key Laboratory of clinical Pharmacy, Health Road, Chang’an District, Shijiazhuang City, Hebei Province, People’s Republic of China

    Naling Fan, Liying Du, Teng Guo, Mingfeng Liu & Xinran Chen

Authors
  1. Naling Fan
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  2. Liying Du
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  3. Teng Guo
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  4. Mingfeng Liu
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Contributions

Conceptualization: XC, LD, ML. Data curation: XC, NF, TG. Funding acquisition: XC. Investigation: XC, NF, TG. Writing–original draft: NF. Writing–review and editing: XC, NF.

Corresponding author

Correspondence to Xinran Chen.

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Conflict of Interest

All authors declared no conflicts of interest.

Ethical Statement

The study was approved by the Animal Ethics Committee of the Fourth Hospital of Hebei Medical University (grant no. 2023206). The study entitled was “Monitoring of imatinib plasma concentration for individualized treatment of gastrointestinal stromal tumors.”

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Fan, N., Du, L., Guo, T. et al. Pharmacokinetic Interaction Between Imatinib and Metformin in Rats. Eur J Drug Metab Pharmacokinet 49, 171–179 (2024). https://doi.org/10.1007/s13318-023-00869-x

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