Skip to content
2000
Volume 25, Issue 10
  • ISSN: 1389-2002
  • E-ISSN: 1875-5453

Abstract

The most significant feature of the high-altitude environment is hypoxia, which affects the activity and expression of drug-metabolizing enzymes and transporters, leading to changes in pharmacokinetic parameters. Notably, gut microbiota is a hidden organ in the body. High-altitude hypoxia will change the composition and quantity of gut microbiota, affect drug metabolism, and change the bioavailability of drugs. This will provide a new perspective on changes in pharmacokinetics at high-altitude. Most studies have revealed that for drugs with low bioavailability and high clearance, the dosage may be increased accordingly. Conversely, the dosage may be reduced to achieve individualized medication. Therefore, this article reviews the changes and mechanisms of drug-metabolizing enzymes, transporters, and gut microbiota in a high-altitude environment and explains the impact of their changes on pharmacokinetics, aiming to provide theories and bases for the adjustment of drug dosage and the rational use of drugs in the clinic under high-altitude environment.

Loading

Article metrics loading...

/content/journals/cdm/10.2174/0113892002356402250130075811
2025-02-11
2025-10-10
Loading full text...

Full text loading...

References

  1. TremblayJ.C. AinslieP.N. Global and country-level estimates of human population at high altitude.Proc. Natl. Acad. Sci. USA202111818e210246311810.1073/pnas.2102463118 33903258
    [Google Scholar]
  2. BarryP.W. PollardA.J. Altitude illness.BMJ2003326739591591910.1136/bmj.326.7395.915 12714473
    [Google Scholar]
  3. ZhangJ.L. LiX.Y. A review of drug metabolism under hypoxia environment at high altitude.Acta Pharm Sin20155091073107910.16438/j.0513‑4870.2015.09.009 26757541
    [Google Scholar]
  4. LuksA.M. AuerbachP.S. FreerL. GrissomC.K. KeyesL.E. McIntoshS.E. RodwayG.W. SchoeneR.B. ZafrenK. HackettP.H. Wilderness medical society clinical practice guidelines for the prevention and treatment of acute altitude illness: 2019 Update.Wilderness Environ. Med.2019304_supplS3S1810.1016/j.wem.2019.04.006 31248818
    [Google Scholar]
  5. LuksA.M. HackettP.H. Medical conditions and high-altitude travel.N. Engl. J. Med.2022386436437310.1056/NEJMra2104829 35081281
    [Google Scholar]
  6. MairbäurlH. Red blood cell function in hypoxia at altitude and exercise.Int. J. Sports Med.1994152516310.1055/s‑2007‑1021020 8157369
    [Google Scholar]
  7. ImrayC. WrightA. SubudhiA. RoachR. Acute mountain sickness: Pathophysiology, prevention, and treatment.Prog. Cardiovasc. Dis.201052646748410.1016/j.pcad.2010.02.003 20417340
    [Google Scholar]
  8. BaiX. LiuG.Q. YangJ.X. DuanY.B. ZhuJ.B. LiX.Y. The effect of high-altitude hypoxia on drug metabolism is mediated by gut microbiota.Acta Pharm. Sin.202156102787279610.16438/j.0513‑4870.2021‑0805
    [Google Scholar]
  9. PowellJ.R. VozehS. HopewellP. CostelloJ. SheinerL.B. RiegelmanS. Theophylline disposition in acutely ill hospitalized patients. The effect of smoking, heart failure, severe airway obstruction, and pneumonia.Am. Rev. Respir. Dis.1978118222923810.1164/arrd.1978.118.2.229 697173
    [Google Scholar]
  10. RicherM. LamY.W.F. Hypoxia, arterial pH and theophylline disposition.Clin. Pharmacokinet.199325428329910.2165/00003088‑199325040‑00004 8261713
    [Google Scholar]
  11. RitschelW.A. PaulosC. ArancibiaA. PezzaniM. AgrawalM.A. WetzelsbergerK.M. LückerP.W. Pharmacokinetics of meperidine in healthy volunteers after short- and long-term exposure to high altitude.J. Clin. Pharmacol.199636761061610.1002/j.1552‑4604.1996.tb04225.x 8844443
    [Google Scholar]
  12. RitschelW.A. PaulosC. ArancibiaA. AgrawalM.A. WetzelsbergerK.M. LückerP.W. Pharmacokinetics of acetazolamide in healthy volunteers after short- and long-term exposure to high altitude.J. Clin. Pharmacol.199838653353910.1002/j.1552‑4604.1998.tb05791.x 9650543
    [Google Scholar]
  13. VijA.G. KishoreK. DeyJ. Effect of intermittent hypobaric hypoxia on efficacy & clearance of drugs.Indian J. Med. Res.20121352211216 22446863
    [Google Scholar]
  14. ArancibiaA. GaiM.N. PaulosC. ChávezJ. PinillaE. AngelN. RitschelW.A. Effects of high altitude exposure on the pharmacokinetics of furosemide in healthy volunteers.Int. J. Clin. Pharmacol. Ther.200442631432010.5414/CPP42314 15222723
    [Google Scholar]
  15. ArancibiaA. GaiM.N. ChávezJ. PaulosC. PinillaE. GonzálezC. VillanuevaS. RitschelW.A. Pharmacokinetics of prednisolone in man during acute and chronic exposure to high altitude.Int. J. Clin. Pharmacol. Ther.2005432859110.5414/CPP43085 15726877
    [Google Scholar]
  16. LiW.B. WangR. XieH. ZhangJ.H. XieX.H. WuX.Y. JiaZ.P. Effects on the pharmacokinetics of furosemide after acute exposure to high altitude at 4010 meters in rats.Acta Pharm. Sin.201247121718172110.16438/j.0513‑4870.2012.12.024 23460981
    [Google Scholar]
  17. LuoB. LiJ. YangT. LiW. ZhangJ. WangC. ZhaoA. WangR. Evaluation of renal excretion and pharmacokinetics of furosemide in rats after acute exposure to high altitude at 4300 m.Biopharm. Drug Dispos.201839837838710.1002/bdd.2154 30120768
    [Google Scholar]
  18. GolaS. KeshriG.K. GuptaA. Hepatic metabolism of ibuprofen in rats under acute hypobaric hypoxia.Exp. Toxicol. Pathol.201365675175810.1016/j.etp.2012.11.001 23218936
    [Google Scholar]
  19. GolaS. GuptaA. KeshriG.K. NathM. VelpandianT. Evaluation of hepatic metabolism and pharmacokinetics of ibuprofen in rats under chronic hypobaric hypoxia for targeted therapy at high altitude.J. Pharm. Biomed. Anal.201612111412210.1016/j.jpba.2016.01.018 26799979
    [Google Scholar]
  20. ZhangJ.H. WangR. XieH. JiaZ.P. LiW.B. LuH. Effects of aminophylline on the pharmacokinetic parameters at high altitude.Pharm J. Chin. PLA.2014212512710.3969/j.issn.1008‑9926.2014.02.008
    [Google Scholar]
  21. ZhangJ. WangR. XieH. YinQ. JiaZ. LiW. Effect of acute exposure to high altitude on pharmacokinetics of propranolol and metoprolol in rats.J. South. Med. Univ.201434111616162010.3969/j.issn.1673‑4254.2014.11.12 25413060
    [Google Scholar]
  22. LuoB.F. ZhangJ. YangT. ZhangJ.H. LiW.B. WangC. Effect of amoxicillin on the expression of PEPT1 and pharmacokinetics upon acute hypoxia at high altitude in rat.Acta Pharm. Sin.201752111715172110.16438/j.0513‑4870.2017‑0562
    [Google Scholar]
  23. WenbinL. RongW. HuaX. JuanhongZ. XiaoyuW. ZhengpingJ. Effects on pharmacokinetics of propranolol and other factors in rats after acute exposure to high altitude at 4,010 m.Cell Biochem. Biophys.2015721273610.1007/s12013‑014‑0397‑3 25417059
    [Google Scholar]
  24. ZhuJ. YangJ. NianY. LiuG. DuanY. BaiX. WangQ. ZhouY. WangX. QuN. LiX. Pharmacokinetics of Acetaminophen and Metformin Hydrochloride in rats after exposure to simulated high altitude hypoxia.Front. Pharmacol.20211269234910.3389/fphar.2021.692349 34220516
    [Google Scholar]
  25. NianY.Q. XinY.Y. YangJ.X. ZhuL. LiuG.Q. LiX.Y. Effect of the simulated high altitude hypoxia on pharmacokinetics of Acetaminophen.Huaxi Yaoxue Zazhi2019340214114610.13375/j.cnki.wcjps.2019.02.007
    [Google Scholar]
  26. ShenY. LuoX. QinN. HuL. LuoL. WangZ. SunY. WangR. LiW. Effects of plateau hypoxia on population pharmacokinetics and pharmacodynamics of metformin in patients with Type 2 diabetes.Zhong Nan Da Xue Xue Bao Yi Xue Ban202348448149010.11817/j.issn.1672‑7347.2023.220267 37385610
    [Google Scholar]
  27. LiuF. SuiX. WangQ. LiJ. YangW. YangY. XiaoZ. SunY. GuoX. YangX. YangJ. WangY. LuoY. Insights into the pharmacodynamics and pharmacokinetics of meldonium after exposure to acute high altitude.Front. Pharmacol.202314111904610.3389/fphar.2023.1119046 36909160
    [Google Scholar]
  28. LiX.Y. GaoF. LiZ.Q. GuanW. FengW.L. GeR.L. Comparison of the pharmacokinetics of sulfamethoxazole in male chinese volunteers at low altitude and acute exposure to high altitude versus subjects living chronically at high altitude: An open-label, controlled, prospective study.Clin. Ther.200931112744275410.1016/j.clinthera.2009.11.019 20110016
    [Google Scholar]
  29. LiX.Y. LiuY.N. LiY.P. YuanM. ZhuJ.B. Pharmacokinetics of sulfamethoxazole in healthy Han volunteers living at plain and in native Han and Tibetan healthy volunteers living at high altitude.Yao Xue Xue Bao20114691117112210.16438/j.0513‑4870.2011.09.021 22121785
    [Google Scholar]
  30. ZhangJ. ZhuJ. YaoX. DuanY. ZhouX. YangM. LiX. Pharmacokinetics of lidocaine hydrochloride metabolized by CYP3A4 in Chinese han volunteers living at low altitude and in Native Han and Tibetan Chinese volunteers living at high altitude.Pharmacology2016973-410711310.1159/000443332 26730802
    [Google Scholar]
  31. LiL.J. Study on the effect of different altitudes on the metabolism of propofol.PhD Thesis Lanzhou University2021
    [Google Scholar]
  32. LiL.J. LiuZ. WangS. WangX.J. Research progress of the impact of plateau environment on propofol pharmacokinetics. Preop.Safety. (QA)2021503181185
    [Google Scholar]
  33. ZhangM.X. Effect of plateau hypoxia on drug transporters in blood brain barrier.Thesis Lanzhou University2018
    [Google Scholar]
  34. HuL. Study on pharmacokinetic and cerebral blood distribution of antiepileptic drugs in high altitude hypoxic environment. Lanzhou City.Theisis Lanzhou University2022
    [Google Scholar]
  35. ZhapA.P. HuL. YaoW.T. ChangX.W. WangR. LiW.B. Effects of plateau hypoxia on pharmacokinetic parameters and cerebral-blood distribution of levetiracetam in rats.J. Cent South Univ. Med. Sci.2023481014451452
    [Google Scholar]
  36. GaoZ.Z. Study on the correlation between the pharmacokinetics of nifedipine and blood pressure changes in high altitude hypoxia.Theis Lanzhou University2021
    [Google Scholar]
  37. ZhouY. ZhuJ.B. DuanY.B. YangJ.X. BaiX. LiuG.Q. Effects of high altitude hypoxia on the pharmacokinetics of losartan potassium.Chin High Alt Med Biol.2021420422323310.13452/j.cnki.jqmc.2021.04.002
    [Google Scholar]
  38. ShaoT. QinY. Pharmacokinetics of roxithromycin in rats under hypoxic and normoxic conditions.Chin Pharmacol Bull.2016321115961601
    [Google Scholar]
  39. HuangL. ZhangX. LuoL. MuH. LiW. WangR. Effects of high-altitude environment on pharmacokinetic parameters of gliquidone in rats.J. Zhejiang Univ. Sci.202251438939610.3724/zdxbyxb‑2022‑0129 37202102
    [Google Scholar]
  40. ZhangX.J. HuangL.J. MuH.F. WangR. Effect of acute exposure to high-altitude on pharmacokinetic parameters of miglitel Rats.Mil Med J. South China.202337864310.13730/j.issn.2097‑2148.2023.08.002
    [Google Scholar]
  41. WangQ.Q. WanC.F. ZhuB. LiM. Pharmacokinetic study of albendazole in mice under hypoxic conditions.J. High Alt Med.2016260337
    [Google Scholar]
  42. HuangQ. LuoL. WangZ.Y. LiW.B. WangR. Research progress of diabetic renal fibrosis.Chin Pharmacol Bull.2023390712271233
    [Google Scholar]
  43. TyzackJ.D. KirchmairJ. Computational methods and tools to predict cytochrome P450 metabolism for drug discovery.Chem. Biol. Drug Des.201993437738610.1111/cbdd.13445 30471192
    [Google Scholar]
  44. KurdiJ. MauriceH. El-KadiA.O.S. OngH. DalkaraS. BélangerP.M. Du SouichP. Effect of hypoxia alone or combined with inflammation and 3‐methylcholanthrene on hepatic cytochrome P450 in conscious rabbits.Br. J. Pharmacol.1999128236537310.1038/sj.bjp.0702795 10510446
    [Google Scholar]
  45. FradetteC. BatongaJ. TengS. Piquette-MillerM. du SouichP. Animal models of acute moderate hypoxia are associated with a down-regulation of CYP1A1, 1A2, 2B4, 2C5, and 2C16 and up-regulation of CYP3A6 and P-glycoprotein in liver.Drug Metab. Dispos.200735576577110.1124/dmd.106.013508 17303624
    [Google Scholar]
  46. LiX.Y. LiuY.N. YuanM. LiY.P. YangY.Z. ZhuJ.B. Effect of high altitude hypoxia on the activity and protein expression of CYP2C9 and CYP2C19.Acta. Pharm. Sin201247218819310.16438/j.0513‑4870.2012.02.015 22512029
    [Google Scholar]
  47. LiX. WangX. LiY. ZhuJ. SuX. YaoX. FanX. DuanY. The activity, protein, and mRNA expression of CYP2E1 and CYP3A1 in rats after exposure to acute and chronic high altitude hypoxia.High Alt. Med. Biol.201415449149610.1089/ham.2014.1026 25330250
    [Google Scholar]
  48. ChenP. LiY.P. ZhuJ.B. LiX.Y. The effect of acute exposure to high alititude on the activity and protein expression of CYP2D6. J. Qinghai. Norma.Univ201430044145[Natural Science Edition].10.16229/j.cnki.issn1001‑7542.2014.04.016
    [Google Scholar]
  49. ZhuJ. DuanY. DuoD. YangJ. BaiX. LiuG. WangQ. WangX. QuN. ZhouY. LiX. High-altitude hypoxia influences the activities of the drug-metabolizing enzyme CYP3A1 and the pharmacokinetics of four cardiovascular system drugs.Pharmaceuticals20221510130310.3390/ph15101303 36297415
    [Google Scholar]
  50. ZhangJ.L. The activity and expression of CYP1A2, CYP2C11, CYP2C22 and CYP3A1 in rats after exposure to high altitude hypoxia.Qinghai University2017
    [Google Scholar]
  51. LuoB.F. YinQ. WangR. LiW.B. LuH. JiaZ.P. Effect of hypoxia on expressions of MDR1 and MRP2 in rats.J. South. Med. Uni.20163691169117210.3969/j.issn.1673‑4254.2016.09.01 27687645
    [Google Scholar]
  52. LiX. WangX. LiY. YuanM. ZhuJ. SuX. YaoX. FanX. DuanY. Effect of exposure to acute and chronic high-altitude hypoxia on the activity and expression of CYP1A2, CYP2D6, CYP2C9, CYP2C19 and NAT2 in rats.Pharmacology2014931-2768310.1159/000358128 24557547
    [Google Scholar]
  53. YuG. ZhouX. Gender difference in the pharmacokinetics and metabolism of VX‐548 in rats.Biopharm. Drug Dispos.202445210711410.1002/bdd.2387 38573807
    [Google Scholar]
  54. CzerniakR. Gender-based differences in pharmacokinetics in laboratory animal models.Int. J. Toxicol.200120316116310.1080/109158101317097746 11488558
    [Google Scholar]
  55. KushidaH. MatsumotoT. IkarashiY. NishimuraH. YamamotoM. Gender differences in plasma pharmacokinetics and hepatic metabolism of geissoschizine methyl ether from Uncaria hook in rats.J. Ethnopharmacol.202126411335410.1016/j.jep.2020.113354 32898626
    [Google Scholar]
  56. LiuW. KulkarniK. HuM. Gender-dependent differences in uridine 5′-diphospho-glucuronosyltransferase have implications in metabolism and clearance of xenobiotics.Expert Opin. Drug Metab. Toxicol.20139121555156910.1517/17425255.2013.829040 24011176
    [Google Scholar]
  57. du SouichP. FradetteC. The effect and clinical consequences of hypoxia on cytochrome P450, membrane carrier proteins activity and expression.Expert Opin. Drug Metab. Toxicol.2011791083110010.1517/17425255.2011.586630 21619472
    [Google Scholar]
  58. ChenL. RaoH. ZhangW. LiuF. JiangD. WeiL. Association of ATP-binding Cassette Transporter (ABC) gene polymorphisms with viral load in patients with genotype 1 hepatitis C virus infection.Clin. Lab.20166209/20161643164910.7754/Clin.Lab.2016.16010528164591
    [Google Scholar]
  59. DrozdzikM. CzekawyI. OswaldS. DrozdzikA. Intestinal drug transporters in pathological states: An overview.Pharmacol. Rep.20207251173119410.1007/s43440‑020‑00139‑6 32715435
    [Google Scholar]
  60. GiacominiK.M. YeeS.W. KoleskeM.L. ZouL. MatssonP. ChenE.C. KroetzD.L. MillerM.A. GozalpourE. ChuX. New and emerging research on solute carrier and atp binding cassette transporters in drug discovery and development: Outlook from the international transporter consortium.Clin. Pharmacol. Ther.2022112354056110.1002/cpt.2627 35488474
    [Google Scholar]
  61. GyimesiG. HedigerM.A. Transporter-mediated drug delivery.Molecules2023283115110.3390/molecules28031151 36770817
    [Google Scholar]
  62. MinQ. FengS.L. LuH. LiW.B. WangC. ZhangJ.H. WangR. Modulation of drug-metabolizing enzymes and transporters under hypoxia environment.Acta Physiologica Sinica.201971233634210.13294/j.aps.2018.0082 31008494
    [Google Scholar]
  63. ZhangM.X. WangR. LiW.B. LuH. XieH. LuoB.F. Research progress on the effect of plateau hypoxia on drug transporters. Chinese Pharmacol.Bulletin2018340331632110.3969/j.issn.1001‑1978.2018.03.005
    [Google Scholar]
  64. JinT. LuoB.F. ZhangX.Y. LiW.B. ZhangJ.H. ZhangM.X. Difference in effects of hypoxia on gene expressions of six drug transporters in rats.Pharm. J. Chin PLA.2017330429730110.3969/j.issn.1008‑9926.2017.04.001
    [Google Scholar]
  65. ZhouX.J. NianN.Q. YangM. XinY.Y. QiaoY.J. ZhuL. The protein and mRNA expression of drug transports MDR1, MRP1 and BCRP after exposure to high-altitude hypoxia.Chin. High. Alt. Med. Biol.2017380318318710.13452/j.cnki.jqmc.2017.03.007
    [Google Scholar]
  66. LiW.B. LuoB.F. WangR. LuH. WangC. ZhaoA.P. JiaZ.P. Changes of P-gp expression in rats’ small intestine and effects on uptake of levofloxacin after acute exposure to hypoxia.Acta Pharm Sin.20165191412141610.16438/j.0513‑4870.2016‑0344 29924524
    [Google Scholar]
  67. ZhangJ. ZhangM. ZhangJ. WangR. Enhanced P-glycoprotein expression under high-altitude hypoxia contributes to increased phenytoin levels and reduced clearance in rats.Eur. J. Pharm. Sci.202015310549010.1016/j.ejps.2020.105490 32721527
    [Google Scholar]
  68. WuW. ShenQ.Q. XuL.Y. DuJ. JiangZ.Z. ZhangL.Y. Research progress on the impact of inflammation on drug transporters.Chin J. Pharmacol Toxicol.2018320540741410.3867/j.issn.1000‑3002.2018.05.009
    [Google Scholar]
  69. NiesA.T. SchaeffelerE. SchwabM. Hepatic solute carrier transporters and drug therapy: Regulation of expression and impact of genetic variation.Pharmacol. Ther.202223810826810.1016/j.pharmthera.2022.108268 35995278
    [Google Scholar]
  70. TsangY.P. UnadkatJ. MaoQ. Regulation of human renal drug transporter mRNA expression by proinflammatory cytokines.J. Pharmacol. Exp. Ther.2023385S358310.1124/jpet.122.146890
    [Google Scholar]
  71. WangF. ZhangH. XuT. HuY. JiangY. Acute exposure to simulated high-altitude hypoxia alters gut microbiota in mice.Arch. Microbiol.2022204741210.1007/s00203‑022‑03031‑4 35731330
    [Google Scholar]
  72. LiuG.Q. LiX.Y. Intestinal flora and drug metabolism under high altitude hypoxia.J. Pharm. Res.2019381271471810.13506/j.cnki.jpr.2019.12.008
    [Google Scholar]
  73. WilsonI.D. NicholsonJ.K. Gut microbiome interactions with drug metabolism, efficacy, and toxicity.Transl. Res.201717920422210.1016/j.trsl.2016.08.002 27591027
    [Google Scholar]
  74. BruntonL. KnollmannB. Goodman and Gilman’s The Pharmacological Basis of Therapeutics.14th edMcGraw Hill LLC2022
    [Google Scholar]
  75. ZhangZ. TangW. Drug metabolism in drug discovery and development.Acta Pharm. Sin. B20188572173210.1016/j.apsb.2018.04.003 30245961
    [Google Scholar]
  76. BagarolliR.A. TobarN. OliveiraA.G. AraújoT.G. CarvalhoB.M. RochaG.Z. VecinaJ.F. CalistoK. GuadagniniD. PradaP.O. SantosA. SaadS.T.O. SaadM.J.A. Probiotics modulate gut microbiota and improve insulin sensitivity in DIO mice.J. Nutr. Biochem.201750162510.1016/j.jnutbio.2017.08.006 28968517
    [Google Scholar]
  77. HaiserH.J. TurnbaughP.J. Developing a metagenomic view of xenobiotic metabolism.Pharmacol. Res.2013691213110.1016/j.phrs.2012.07.009 22902524
    [Google Scholar]
  78. GingellR. BridgesJ.W. WilliamsR.T. The role of the gut flora in the metabolism of prontosil and neoprontosil in the rat.Xenobiotica19711214315610.3109/00498257109044386 5173017
    [Google Scholar]
  79. ZimmermannM. Zimmermann-KogadeevaM. WegmannR. GoodmanA.L. Separating host and microbiome contributions to drug pharmacokinetics and toxicity.Science20193636427eaat993110.1126/science.aat9931 30733391
    [Google Scholar]
  80. TakenoS. SakaiT. Involvement of the intestinal microflora in nitrazepam‐induced teratogenicity in rats and its relationship to nitroreduction.Teratology199144220921410.1002/tera.1420440209 1925980
    [Google Scholar]
  81. ZhaoR. CokerO.O. WuJ. ZhouY. ZhaoL. NakatsuG. BianX. WeiH. ChanA.W.H. SungJ.J.Y. ChanF.K.L. El-OmarE. YuJ. Aspirin reduces colorectal tumor development in mice and gut microbes reduce its bioavailability and chemopreventive effects.Gastroenterology20201593969983.e410.1053/j.gastro.2020.05.004 32387495
    [Google Scholar]
  82. TianJ. LiC. DongZ. YangY. XingJ. YuP. XinY. XuF. WangL. MuY. GuoX. SunQ. ZhaoG. GuY. QinG. JiangW. Inactivation of the antidiabetic drug acarbose by human intestinal microbial-mediated degradation.Nat. Metab.20235589690910.1038/s42255‑023‑00796‑w 37157031
    [Google Scholar]
  83. van KesselS.P. FryeA.K. El-GendyA.O. CastejonM. KeshavarzianA. van DijkG. El AidyS. Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of parkinson’s disease.Nat. Commun.201910131010.1038/s41467‑019‑08294‑y 30659181
    [Google Scholar]
  84. FengR. ShouJ.W. ZhaoZ.X. HeC.Y. MaC. HuangM. FuJ. TanX.S. LiX.Y. WenB.Y. ChenX. YangX.Y. RenG. LinY. ChenY. YouX.F. WangY. JiangJ.D. Transforming berberine into its intestine-absorbable form by the gut microbiota.Sci. Rep.2015511215510.1038/srep12155 26174047
    [Google Scholar]
  85. LiT. ChiangJ.Y.L. MaQ. Bile acid signaling in metabolic disease and drug therapy.Pharmacol. Rev.201466494898310.1124/pr.113.008201 25073467
    [Google Scholar]
  86. LiX. LiuL. CaoZ. LiW. LiH. LuC. YangX. LiuY. Gut microbiota as an “invisible organ” that modulates the function of drugs.Biomed. Pharmacother.202012110965310.1016/j.biopha.2019.109653 31810138
    [Google Scholar]
  87. WangY. ShouJ.W. LiX.Y. ZhaoZ.X. FuJ. HeC.Y. FengR. MaC. WenB.Y. GuoF. YangX.Y. HanY.X. WangL.L. TongQ. YouX.F. LinY. KongW.J. SiS.Y. JiangJ.D. Berberine-induced bioactive metabolites of the gut microbiota improve energy metabolism.Metabolism201770728410.1016/j.metabol.2017.02.003 28403947
    [Google Scholar]
  88. ZhangX. ZhaoY. XuJ. XueZ. ZhangM. PangX. ZhangX. ZhaoL. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats.Sci. Rep.2015511440510.1038/srep14405 26396057
    [Google Scholar]
  89. McCreightL.J. BaileyC.J. PearsonE.R. Metformin and the gastrointestinal tract.Diabetologia201659342643510.1007/s00125‑015‑3844‑9 26780750
    [Google Scholar]
  90. LeiM.Y. SunZ.Y. QiuY. LiuC. The influence of metformin on the gut microbiome of T2D patients.Chin. J. Microecol.2018300897798010.13381/j.cnki.cjm.201808026
    [Google Scholar]
  91. WeersmaR.K. ZhernakovaA. FuJ. Interaction between drugs and the gut microbiome.Gut20206981510151910.1136/gutjnl‑2019‑320204 32409589
    [Google Scholar]
  92. AdakA. MaityC. GhoshK. PatiB.R. MondalK.C. Dynamics of predominant microbiota in the human gastrointestinal tract and change in luminal enzymes and immunoglobulin profile during high-altitude adaptation.Folia Microbiol. (Praha)201358652352810.1007/s12223‑013‑0241‑y 23536261
    [Google Scholar]
  93. LanD. JiW. LinB. ChenY. HuangC. XiongX. FuM. MipamT.D. AiY. ZengB. LiY. CaiZ. ZhuJ. ZhangD. LiJ. Correlations between gut microbiota community structures of Tibetans and geography.Sci. Rep.2017711698210.1038/s41598‑017‑17194‑4 29209019
    [Google Scholar]
  94. ZhangJ. ChenY. SunY. WangR. ZhangJ. JiaZ. Plateau hypoxia attenuates the metabolic activity of intestinal flora to enhance the bioavailability of nifedipine.Drug Deliv.20182511175118110.1080/10717544.2018.1469687 29790376
    [Google Scholar]
  95. SuzukiT.A. MartinsF.M. NachmanM.W. Altitudinal variation of the gut microbiota in wild house mice.Mol. Ecol.20192892378239010.1111/mec.14905 30346069
    [Google Scholar]
  96. SunY. ZhangJ. ZhaoA. LiW. FengQ. WangR. Effects of intestinal flora on the pharmacokinetics and pharmacodynamics of aspirin in high-altitude hypoxia.PLoS One2020153e023019710.1371/journal.pone.0230197 32163488
    [Google Scholar]
  97. BaiX. LiuG. YangJ. ZhuJ. WangQ. ZhouY. GuW. LaL. LiX. Changes in the Gut microbiota of rats in high-altitude hypoxic environments.Microbiol. Spectr.2022106e016262210.1128/spectrum.01626‑22 36301100
    [Google Scholar]
  98. BaiX. YangJ. LiuG. ZhuJ. WangQ. GuW. LaL. LiX. Regulation of CYP450 and drug transporter mediated by gut microbiota under high-altitude hypoxia.Front. Pharmacol.20221397737010.3389/fphar.2022.977370 36188572
    [Google Scholar]
  99. ZhangJ. SunY. HeJ. WuG. WangR. ZhangJ. Comprehensive investigation of the influence of high-altitude hypoxia on clopidogrel metabolism and gut microbiota.Curr. Drug Metab.2023241072373310.2174/0113892002272030231005103840 37842900
    [Google Scholar]
  100. ZhangJ.H. ZhangY.T. ZhangJ.M. WangR. In vivo metabolism of pyridostigmine bromide mediated by intestinal flora in condition of high altitude.Drug. Eval. Res.202210.7501/j.issn.1674‑6376.2022.03.004
    [Google Scholar]
  101. WangC. WangR. XieH. SunY. TaoR. LiuW. LiW. LuH. JiaZ. Effect of acetazolamide on cytokines in rats exposed to high altitude.Cytokine20168311011710.1016/j.cyto.2016.04.003 27104804
    [Google Scholar]
  102. MinQ. The regulatpry mechanism of cyp3a1 and ugt1a1 in hypobaric hypoxia.Thesis Lanzhou University2019
    [Google Scholar]
  103. LiJ.J. Effects of acute and chronic hypoxia on drug metabolic enzymes in rats and regulation of serum media on CYP450.Thesis Lanzhou University2018
    [Google Scholar]
  104. LeeP. ChandelN.S. SimonM.C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond.Nat. Rev. Mol. Cell Biol.202021526828310.1038/s41580‑020‑0227‑y 32144406
    [Google Scholar]
  105. YuanX. LuH. ZhaoA. DingY. MinQ. WangR. Transcriptional regulation of CYP3A4 by nuclear receptors in human hepatocytes under hypoxia.Drug Metab. Rev.202052222523410.1080/03602532.2020.1733004 32270716
    [Google Scholar]
  106. DuanY. ZhuJ. YangJ. LiuG. BaiX. QuN. WangX. LiX. Regulation of high-altitude hypoxia on the transcription of CYP450 and UGT1A1 mediated by PXR and CAR.Front. Pharmacol.20201157417610.3389/fphar.2020.574176 33041817
    [Google Scholar]
  107. YangJ.X. Transcriptional Regulation of HNF1α and HNF4α on CYP450 under High-Altitude Hypoxia. Xining City..Thesis Qinghai University2023
    [Google Scholar]
  108. LiW. LiJ. WangR. XieH. JiaZ. MDR1 will play a key role in pharmacokinetic changes under hypoxia at high altitude and its potential regulatory networks.Drug Metab. Rev.201547219119810.3109/03602532.2015.1007012 25639892
    [Google Scholar]
  109. DuanY. BaiX. YangJ. ZhouY. GuW. LiuG. WangQ. ZhuJ. LaL. LiX. Exposure to High-Altitude Environment Is Associated with Drug Transporters Change: microRNA-873-5p-Mediated Alteration of Function and Expression Levels of Drug Transporters under Hypoxia.Drug Metab. Dispos.202250217418610.1124/dmd.121.000681 34844996
    [Google Scholar]
  110. MatoukI.J. DeGrootN. MezanS. AyeshS. Abu-lailR. HochbergA. GalunE. The H19 non-coding RNA is essential for human tumor growth.PLoS One200729e84510.1371/journal.pone.0000845 17786216
    [Google Scholar]
  111. KuoT.C. KungH.J. ShihJ.W. Signaling in and out: Long-noncoding RNAs in tumor hypoxia.J. Biomed. Sci.20202715910.1186/s12929‑020‑00654‑x 32370770
    [Google Scholar]
  112. ZhangY.T. Effect of gut microbiota-bile acid-FXR axis on the expression of CYP3A1 in rat intestinal under high altitude hypoxia.Lanzhou City.. Thesis Lanzhou University2021
    [Google Scholar]
/content/journals/cdm/10.2174/0113892002356402250130075811
Loading
/content/journals/cdm/10.2174/0113892002356402250130075811
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test