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image of Pharmacokinetics of Trelagliptin in Rats after Exposure to Acute and Chronic High Altitude Hypoxia

Abstract

background

As a long-acting DPP-4 inhibitor administered orally once a week, trelagliptin can address the issues of frequent medication and poor compliance associated with traditional hypoglycemic drugs.

Methods

The Hypoxia model in rats was constructed at an altitude of approximately 4300 meters. The plasma concentration of trelagliptin was determined by LC-MS/MS. The biochemical indices and the protein expression levels of P-gp and OCT2 in the kidneys of rats were determined to explain the possible reasons for the pharmacokinetic changes of trelagliptin.

Results

This study demonstrated that the pharmacokinetic parameters of trelagliptin were significantly changed in high-altitude hypoxic environments. Compared with the control group, the AUC, MRT, t1/2, and Vd were remarkably increased during acute and chronic hypoxia, while the CL and Ke were decreased. Additionally, the biochemical indexes and protein expression of P-gp and OCT2 were significantly altered.

Conclusion

The study demonstrated that high-altitude hypoxia significantly altered trelagliptin's pharmacokinetics, slowing clearance, prolonging elimination half-life and residence time, and increasing bioavailability. These changes suggested that the optimal therapeutic dosage of trelagliptin should be reassessed under hypoxic exposure.

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2025-10-15
2025-12-14

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References

  1. Diagnosis and classification of Diabetes mellitus. Diabetes Care 2013 36 Suppl. 1 S67 S74 American Diabetes Association. 10.2337/dc13‑S067 23264425
    [Google Scholar]
  2. Sun H. Saeedi P. Karuranga S. Pinkepank M. Ogurtsova K. Duncan B.B. Stein C. Basit A. Chan J.C.N. Mbanya J.C. Pavkov M.E. Ramachandaran A. Wild S.H. James S. Herman W.H. Zhang P. Bommer C. Kuo S. Boyko E.J. Magliano D.J. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. Pract. 2022 183 109119 10.1016/j.diabres.2021.109119 34879977
    [Google Scholar]
  3. Dong C. Wu G. Li H. Qiao Y. Gao S. Type 1 and type 2 diabetes mortality burden: Predictions for 2030 based on Bayesian age‐period‐cohort analysis of China and global mortality burden from 1990 to 2019. J. Diabetes Investig. 2024 15 5 623 633 10.1111/jdi.14146 38265170
    [Google Scholar]
  4. Kotwas A. Karakiewicz B. Zabielska P. Wieder-Huszla S. Jurczak A. Epidemiological factors for type 2 Diabetes mellitus: Evidence from the global burden of disease. Arch. Public Health 2021 79 1 110 10.1186/s13690‑021‑00632‑1 34158120
    [Google Scholar]
  5. Woolcott O.O. Castillo O.A. Gutierrez C. Elashoff R.M. Stefanovski D. Bergman R.N. Inverse association between diabetes and altitude: A cross‐sectional study in the adult population of the United States. Obesity 2014 22 9 2080 2090 10.1002/oby.20800 24890677
    [Google Scholar]
  6. Okumiya K. Sakamoto R. Ishimoto Y. Kimura Y. Fukutomi E. Ishikawa M. Suwa K. Imai H. Chen W. Kato E. Nakatsuka M. Kasahara Y. Fujisawa M. Wada T. Wang H. Dai Q. Xu H. Qiao H. Ge R.L. Norboo T. Tsering N. Kosaka Y. Nose M. Yamaguchi T. Tsukihara T. Ando K. Inamura T. Takeda S. Ishine M. Otsuka K. Matsubayashi K. Glucose intolerance associated with hypoxia in people living at high altitudes in the Tibetan highland. BMJ Open 2016 6 2 e009728 10.1136/bmjopen‑2015‑009728 26908520
    [Google Scholar]
  7. Sherpa L.Y. Deji; Stigum, H.; Chongsuvivatwong, V.; Nafstad, P.; Bjertness, E. Prevalence of metabolic syndrome and common metabolic components in high altitude farmers and herdsmen at 3700 m in Tibet. High Alt. Med. Biol. 2013 14 1 37 44 10.1089/ham.2012.1051 23537259
    [Google Scholar]
  8. Hirschler V. Maccallini G. Molinari C. Hidalgo M. Intersimone P. Gonzalez C. Type 2 Diabetes markers in indigenous Argentinean children living at different altitudes. Running title: Type 2 Diabetes markers in children at different altitudes. AIMS Public Health 2018 5 4 440 453 10.3934/publichealth.2018.4.440 30631785
    [Google Scholar]
  9. Hill N. Deighton K. Matu J. Misra S. Oliver N.S. Newman C. Mellor A. O’Hara J. Woods D. Continuous glucose monitoring at high altitude— Effects on glucose homeostasis. Med. Sci. Sports Exerc. 2018 50 8 1679 1686 10.1249/MSS.0000000000001624 29613998
    [Google Scholar]
  10. Graham G.G. Punt J. Arora M. Day R.O. Doogue M.P. Duong J.K. Furlong T.J. Greenfield J.R. Greenup L.C. Kirkpatrick C.M. Ray J.E. Timmins P. Williams K.M. Clinical pharmacokinetics of metformin. Clin. Pharmacokinet. 2011 50 2 81 98 10.2165/11534750‑000000000‑00000 21241070
    [Google Scholar]
  11. Bugliani M. Syed F. Paula F.M.M. Omar B.A. Suleiman M. Mossuto S. Grano F. Cardarelli F. Boggi U. Vistoli F. Filipponi F. De Simone P. Marselli L. De Tata V. Ahren B. Eizirik D.L. Marchetti P. DPP-4 is expressed in human pancreatic beta cells and its direct inhibition improves beta cell function and survival in type 2 diabetes. Mol. Cell. Endocrinol. 2018 473 186 193 10.1016/j.mce.2018.01.019 29409957
    [Google Scholar]
  12. Kaku K. First novel once-weekly DPP-4 inhibitor, trelagliptin, for the treatment of type 2 diabetes mellitus. Expert Opin. Pharmacother. 2015 16 16 2539 2547 10.1517/14656566.2015.1099630 26523434
    [Google Scholar]
  13. Zhu J. Duan Y. Duo D. Yang J. Bai X. Liu G. Wang Q. Wang X. Qu N. Zhou Y. Li X. High-altitude hypoxia influences the activities of the drug-metabolizing enzyme CYP3A1 and the pharmacokinetics of four cardiovascular system drugs. Pharmaceuticals 2022 15 10 1303 10.3390/ph15101303 36297415
    [Google Scholar]
  14. Wenbin L. Rong W. Hua X. Juanhong Z. Xiaoyu W. Zhengping J. Effects on pharmacokinetics of propranolol and other factors in rats after acute exposure to high altitude at 4,010 m. Cell Biochem. Biophys. 2015 72 1 27 36 10.1007/s12013‑014‑0397‑3 25417059
    [Google Scholar]
  15. Hui X. Liang H. Yan J. Comprehensive lipidomic analysis reveals regulation of glyceride metabolism in rat visceral adipose tissue by high-altitude chronic hypoxia. PLoS One 2022 17 5 e0267513 10.1371/journal.pone.0267513 35511796
    [Google Scholar]
  16. Jun J.C. Shin M.K. Yao Q. Bevans-Fonti S. Poole J. Drager L.F. Polotsky V.Y. Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice. Am. J. Physiol. Endocrinol. Metab. 2012 303 3 E377 E388 10.1152/ajpendo.00641.2011 22621867
    [Google Scholar]
  17. Jun J.C. Shin M.K. Yao Q. Devera R. Fonti-Bevans S. Polotsky V.Y. Thermoneutrality modifies the impact of hypoxia on lipid metabolism. Am. J. Physiol. Endocrinol. Metab. 2013 304 4 E424 E435 10.1152/ajpendo.00515.2012 23249698
    [Google Scholar]
  18. Mohamed O.S. Abdel Baky N.A. Sayed-Ahmed M.M. Al-Najjar A.H. Lactoferrin alleviates cyclophosphamide induced-nephropathy through suppressing the orchestration between Wnt4/β-catenin and ERK1/2/NF-κB signaling and modulating klotho and Nrf2/HO-1 pathway. Life Sci. 2023 319 121528 10.1016/j.lfs.2023.121528 36828132
    [Google Scholar]
  19. Seo I.H. Lee H.B. Kim S. Lee Y.J. Jung D.H. Inverse relationship between hepatic steatosis and alanine aminotransferase with sex hormone-binding globulin in men. Yonsei Med. J. 2017 58 4 731 736 10.3349/ymj.2017.58.4.731 28540984
    [Google Scholar]
  20. Luo B. Wang R. Li W. Yang T. Wang C. Lu H. Zhao A. Zhang J. Jia Z. Pharmacokinetic changes of norfloxacin based on expression of MRP2 after acute exposure to high altitude at 4300 m. Biomed. Pharmacother. 2017 89 1078 1085 10.1016/j.biopha.2017.02.092 28292016
    [Google Scholar]
  21. Kim S.J. Kim K.M. Yang J.H. Cho S.S. Kim J.Y. Park S.J. Lee S.K. Ku S.K. Cho I.J. Ki S.H. Sestrin2 protects against acetaminophen-induced liver injury. Chem. Biol. Interact. 2017 269 50 58 10.1016/j.cbi.2017.02.002 28209544
    [Google Scholar]
  22. Suo Y. Wright N.J. Guterres H. Fedor J.G. Butay K.J. Borgnia M.J. Im W. Lee S.Y. Molecular basis of polyspecific drug and xenobiotic recognition by OCT1 and OCT2. Nat. Struct. Mol. Biol. 2023 30 7 1001 1011 10.1038/s41594‑023‑01017‑4 37291422
    [Google Scholar]
  23. Chen L. Wang Z. Xu Q. Liu Y. Chen L. Guo S. Wang H. Zeng K. Liu J. Zeng S. Yu L. The failure of DAC to induce OCT2 expression and its remission by hemoglobin-based nanocarriers under hypoxia in renal cell carcinoma. Theranostics 2020 10 8 3562 3578 10.7150/thno.39944 32206108
    [Google Scholar]
  24. Sun H. Frassetto L. Benet L.Z. Effects of renal failure on drug transport and metabolism. Pharmacol. Ther. 2006 109 1-2 1 11 10.1016/j.pharmthera.2005.05.010 16085315
    [Google Scholar]
  25. Ji L. Masuda S. Saito H. Inui K.I. Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int. 2002 62 2 514 524 10.1046/j.1523‑1755.2002.00464.x 12110012
    [Google Scholar]
  26. Huang Z.H. Murakami T. Okochi A. Yumoto R. Nagai J. Takano M. Expression and function of P-glycoprotein in rats with glycerol-induced acute renal failure. Eur. J. Pharmacol. 2000 406 3 453 460 10.1016/S0014‑2999(00)00699‑3 11040353
    [Google Scholar]
  27. Wang G. Li S. Yu J. Lactate dehydrogenase-inhibitors isolated from ethyl acetate extract of selaginella doederleinii by using a rapid screening method with enzyme-immobilized magnetic nanoparticles. Front. Biosci. 2022 27 8 229 10.31083/j.fbl2708229
    [Google Scholar]
  28. Adeva-Andany M. López-Ojén M. Funcasta-Calderón R. Ameneiros-Rodríguez E. Donapetry-García C. Vila-Altesor M. Rodríguez-Seijas J. Comprehensive review on lactate metabolism in human health. Mitochondrion 2014 17 76 100 10.1016/j.mito.2014.05.007 24929216
    [Google Scholar]
  29. Ye J. Tang X. Long Y. Chu Z. Zhou Q. Lin B. The effect of hypoxia on the proliferation capacity of dermal papilla cell by regulating lactate dehydrogenase. J. Cosmet. Dermatol. 2021 20 2 684 690 10.1111/jocd.13578 32599679
    [Google Scholar]
  30. Li C. Ni C. Yang M. Tang Y. Li Z. Zhu Y. Jiang Z. Sun B. Li C. Honokiol protects pancreatic β cell against high glucose and intermittent hypoxia-induced injury by activating Nrf2/ARE pathway in vitro and in vivo. Biomed. Pharmacother. 2018 97 1229 1237 10.1016/j.biopha.2017.11.063 29145148
    [Google Scholar]
  31. Iiyori N. Alonso L.C. Li J. Sanders M.H. Garcia-Ocana A. O’Doherty R.M. Polotsky V.Y. O’Donnell C.P. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am. J. Respir. Crit. Care Med. 2007 175 8 851 857 10.1164/rccm.200610‑1527OC 17272786
    [Google Scholar]
  32. Margolis L.M. Karl J.P. Wilson M.A. Coleman J.L. Ferrando A.A. Young A.J. Pasiakos S.M. Metabolomic profiles are reflective of hypoxia-induced insulin resistance during exercise in healthy young adult males. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2021 321 1 R1 R11 10.1152/ajpregu.00076.2021 33949213
    [Google Scholar]
  33. Liu Z. Xu L. Xing M. Xu X. Wei J. Wang J. Kang W. Trelagliptin succinate: DPP-4 inhibitor to improve insulin resistance in adipocytes. Biomed. Pharmacother. 2020 125 109952 10.1016/j.biopha.2020.109952 32036216
    [Google Scholar]
  34. Inagaki N. Onouchi H. Maezawa H. Kuroda S. Kaku K. Once-weekly trelagliptin versus daily alogliptin in Japanese patients with type 2 diabetes: A randomised, double-blind, phase 3, non-inferiority study. Lancet Diabetes Endocrinol. 2015 3 3 191 197 10.1016/S2213‑8587(14)70251‑7 25609193
    [Google Scholar]
  35. McKeage K. Trelagliptin: First global approval. Drugs 2015 75 10 1161 1164 10.1007/s40265‑015‑0431‑9 26115728
    [Google Scholar]
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Pharmacokinetics of Trelagliptin in Rats after Exposure to Acute and Chronic High Altitude Hypoxia
Bentham Science Publishers ; https://doi.org/10.2174/0113892002408318251002114813
/content/journals/cdm/10.2174/0113892002408318251002114813
/content/journals/cdm/10.2174/0113892002408318251002114813
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  • Article Type:     Research Article
Keywords: OCT2 ; DPP-4 inhibitor ; P-gp ; trelagliptin ; pharmacokinetics ; High-altitude hypoxia

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