Skip to content
2000
Volume 31, Issue 40
  • ISSN: 1381-6128
  • E-ISSN: 1873-4286

Abstract

Background

Doxorubicin (DOX) is a widely used anthracycline antibiotic for the treatment of breast cancer, liver cancer, lymphoma, and other malignant tumors. However, its clinical application is limited by the side effects and drug resistance. Astragalus injection has been combined with DOX in the treatment of cancer, which improves the curative effect and reduces drug resistance. This study investigated the interaction between DOX and Astragalus injection and elucidated the potential mechanism.

Methods

The pharmacokinetics of DOX injection (7 mg/kg, intraperitoneal injection) with or without Astragalus injection (4.25 mL/kg/day for 14 days, intraperitoneal injection) were investigated in plasma from male Sprague-Dawley rats ( = 6) by UPLC-MS/MS. The group without the Astragalus injection was set as the control group. Additionally, the effects of Astragalus injection on CYP450 enzyme activities were assessed using a rat liver microsome incubation system with cocktail probe drugs.

Results

Astragalus injection significantly increased the C (2090.01 ± 99.60 5262.77 ± 111.15 ng/mL) and AUC (1190.23 ± 104.43 . 3777.27 ± 130.55 μg/L × h) and prolonged the t (0.09 ± 0.02 . 0.14 ± 0.04 h) of DOX. Astragalus injection significantly inhibited the activity of CYP1A2, CYP2C9, CYP2E1, and CYP3A4, and enhanced the activity of CYP2D1 with a metabolic elimination rate of 30.11 ± 2.67% 19.66 ± 3.41%, 35.95 ± 2.57% 23.26 ± 3.57%, 13.43 ± 2.56% 9.06 ± 2.51%, 47.90 ± 6.30% 25.87 ± 2.55%, 17.62 ± 1.49% 24.12 ± 2.91%, respectively ( < 0.05).

Conclusion

The co-administration of DOX and Astragalus injection alters the systemic exposure of DOX by affecting the metabolism of DOX and the activity of CYP450 enzymes. These findings highlight the importance of drug-drug interactions when combining Astragalus injection with DOX and provide a basis for optimizing combination therapies to address DOX resistance and toxicity.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cpd/10.2174/0113816128362829250527023843
2025-06-04
2025-10-28

  • From This Site

    /content/journals/cpd/10.2174/0113816128362829250527023843
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. ShafeiA. El-BaklyW. SobhyA. A review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer.Biomed. Pharmacother.2017951209121810.1016/j.biopha.2017.09.059 28931213
     [Google Scholar]
  2. YuJ. WangC. KongQ. WuX. LuJ.J. ChenX. Recent progress in doxorubicin-induced cardiotoxicity and protective potential of natural products.Phytomedicine20184012513910.1016/j.phymed.2018.01.009 29496165
     [Google Scholar]
  3. WangN. WeiR.B. LiQ.P. YangX. ChenX.M. Protective effects of astragaloside in rats with adriamycin nephropathy and underlying mechanism.Chin. J. Nat. Med.201614427027710.1016/S1875‑5364(16)30027‑9 27114314
     [Google Scholar]
  4. PugazhendhiA. EdisonT.N.J.I. VelmuruganB.K. JacobJ.A. KaruppusamyI. Toxicity of Doxorubicin (Dox) to different experimental organ systems.Life Sci.2018200263010.1016/j.lfs.2018.03.023 29534993
     [Google Scholar]
  5. ChangH.L. KuoY.H. WuL.H. The extracts of Astragalus membranaceus overcome tumor immune tolerance by inhibition of tumor programmed cell death protein ligand-1 expression.Int. J. Med. Sci.202017793994510.7150/ijms.42978 32308547
     [Google Scholar]
  6. FuJ. WangZ. HuangL. Review of the botanical characteristics, phytochemistry, and pharmacology of Astragalus membranaceus (Huangqi).Phytother. Res.20142891275128310.1002/ptr.5188 25087616
     [Google Scholar]
  7. D’AvinoD. CerquaI. UllahH. Beneficial effects of Astragalus membranaceus (Fisch.) bunge extract in controlling inflammatory response and preventing asthma features.Int. J. Mol. Sci.202324131095410.3390/ijms241310954 37446131
     [Google Scholar]
  8. ZhangX. LiangT. YangW. Astragalus membranaceus injection suppresses production of interleukin-6 by activating autophagy through the AMPK-mTOR pathway in lipopolysaccharide-stimulated macrophages.Oxid. Med. Cell. Longev.202020201364147 32724488
     [Google Scholar]
  9. GuoJ. ZhaoN. JinP. YinY. Effect of Astragalus injection on inflammatory mediators in patients with viral myocarditis: A systematic review and meta-analysis.Phytomedicine202210715443610.1016/j.phymed.2022.154436 36115170
     [Google Scholar]
  10. KhanH.M. RazaS.M. AnjumA.A. AliM.A. Antiviral, embryo toxic and cytotoxic activities of Astragalus membranaceus root extracts.Pak. J. Pharm. Sci.2019321137142 30772802
     [Google Scholar]
  11. LiS. SunY. HuangJ. Anti-tumor effects and mechanisms of Astragalus membranaceus (AM) and its specific immunopotentiation: Status and prospect.J. Ethnopharmacol.202025811279710.1016/j.jep.2020.112797 32243990
     [Google Scholar]
  12. ChoW.C.S. LeungK.N. In vitro and in vivo anti-tumor effects of Astragalus membranaceus.Cancer Lett.20072521435410.1016/j.canlet.2006.12.001 17223259
     [Google Scholar]
  13. SheikA. KimK. VaraprasadG.L. The anti-cancerous activity of adaptogenic herb Astragalus membranaceus.Phytomedicine20219115369810.1016/j.phymed.2021.153698 34479785
     [Google Scholar]
  14. FuS. ZhangJ. Menniti-IppolitoF. Huangqi injection (a traditional Chinese patent medicine) for chronic heart failure: A systematic review.PLoS One201165e1960410.1371/journal.pone.0019604
     [Google Scholar]
  15. CaoA. HeH. WangQ. LiL. AnY. ZhouX. Evidence of Astragalus injection combined platinum-based chemotherapy in advanced nonsmall cell lung cancer patients.Medicine20199811e1479810.1097/MD.0000000000014798 30882655
     [Google Scholar]
  16. McCullochM. SeeC. ShuX. Astragalus-based Chinese herbs and platinum-based chemotherapy for advanced non-small-cell lung cancer: Meta-analysis of randomized trials.J. Clin. Oncol.200624341943010.1200/JCO.2005.03.6392 16421421
     [Google Scholar]
  17. SunS. LiuL. SongH. LiH. Pharmacokinetic study on the co-administration of abemaciclib and astragaloside IV in rats.Pharm. Biol.20226011944194810.1080/13880209.2022.2125539 36226863
     [Google Scholar]
  18. LiY.J. LeiY.H. YaoN. Autophagy and multidrug resistance in cancer.Chin. J. Cancer20173615210.1186/s40880‑017‑0219‑2 28646911
     [Google Scholar]
  19. XieT. LiY. LiS.L. LuoH.F. Astragaloside IV enhances cisplatin chemosensitivity in human colorectal cancer via regulating NOTCH3.Oncol. Res.201624644745310.3727/096504016X14685034103590 28281965
     [Google Scholar]
  20. QuX. GaoH. ZhaiJ. Astragaloside IV enhances cisplatin chemosensitivity in hepatocellular carcinoma by suppressing MRP2.Eur. J. Pharm. Sci.202014810532510.1016/j.ejps.2020.105325 32259679
     [Google Scholar]
  21. LiangY. ChenB. LiangD. Pharmacological effects of astragaloside IV: A review.Molecules20232816611810.3390/molecules28166118 37630371
     [Google Scholar]
  22. ZhengY. DaiY. LiuW. Astragaloside IV enhances taxol chemosensitivity of breast cancer via caveolin‐1‐targeting oxidant damage.J. Cell. Physiol.201923444277429010.1002/jcp.27196 30146689
     [Google Scholar]
  23. ZhouR. GuoT. LiJ. Research progress on the antitumor effects of astragaloside IV.Eur. J. Pharmacol.202393817544910.1016/j.ejphar.2022.175449 36473596
     [Google Scholar]
  24. XiuW. ZhangY. TangD. Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFβ and Hedgehog signal pathway.Cell. Oncol.20244762201221510.1007/s13402‑024‑00999‑7 39373858
     [Google Scholar]
  25. ZhangY. ZhouQ. DingX. WangH. TanG. HILIC-MS-based metabolomics reveal that Astragalus polysaccharide alleviates doxorubicin-induced cardiomyopathy by regulating sphingolipid and glycerophospholipid homeostasis.J. Pharm. Biomed. Anal.202120311417710.1016/j.jpba.2021.114177 34198197
     [Google Scholar]
  26. WangD. CuiQ. YangY.J. LiuA.Q. ZhangG. YuJ.C. Application of dendritic cells in tumor immunotherapy and progress in the mechanism of anti-tumor effect of Astragalus polysaccharide (APS) modulating dendritic cells: A review.Biomed. Pharmacother.202215511354110.1016/j.biopha.2022.113541 36127221
     [Google Scholar]
  27. LiW. HuX. WangS. Characterization and anti-tumor bioactivity of astragalus polysaccharides by immunomodulation.Int. J. Biol. Macromol.202014598599710.1016/j.ijbiomac.2019.09.189 31669273
     [Google Scholar]
  28. LiQ. ZhangC. XuG. Astragalus polysaccharide ameliorates CD8+ T cell dysfunction through STAT3/Gal-3/LAG3 pathway in inflammation‐induced colorectal cancer.Biomed. Pharmacother.202417111617210.1016/j.biopha.2024.116172 38278025
     [Google Scholar]
  29. LinJ. FangL. LiH. Astragaloside IV alleviates doxorubicin induced cardiomyopathy by inhibiting NADPH oxidase derived oxidative stress.Eur. J. Pharmacol.201985917249010.1016/j.ejphar.2019.172490 31229536
     [Google Scholar]
  30. TangQ. ZhangM. HongZ. Effects of astragalus injection on different stages of early hepatocarcinogenesis in a two-stage hepatocarcinogenesis model using rats.J. Toxicol. Pathol.201932315516410.1293/tox.2019‑0006 31402807
     [Google Scholar]
  31. ZengR. LiH. JiaL. Association of CYP24A1 with survival and drug resistance in clinical cancer patients: A meta-analysis.BMC Cancer2022221131710.1186/s12885‑022‑10369‑x 36527000
     [Google Scholar]
  32. MokhosoevI.M. AstakhovD.V. TerentievA.A. MoldogazievaN.T. Human Cytochrome P450 Cancer-Related Metabolic Activities and Gene Polymorphisms: A Review.Cells20241323195810.3390/cells13231958 39682707
     [Google Scholar]
  33. Szeląg-PieniekS. OswaldS. PostM. Łapczuk-RomańskaJ. DroździkM. KurzawskiM. Hepatic drug-metabolizing enzymes and drug transporters in Wilson’s disease patients with liver failure.Pharmacol. Rep.20217351427143810.1007/s43440‑021‑00290‑8 34117631
     [Google Scholar]
  34. AlmazrooO.A. MiahM.K. VenkataramananR. Drug metabolism in the liver.Clin. Liver Dis.201721112010.1016/j.cld.2016.08.001 27842765
     [Google Scholar]
  35. AmacherD.E. The primary role of hepatic metabolism in idiosyncratic drug-induced liver injury.Expert Opin. Drug Metab. Toxicol.20128333534710.1517/17425255.2012.658041 22288564
     [Google Scholar]
  36. KulsharovaG. KurmangaliyevaA. Liver microphysiological platforms for drug metabolism applications.Cell Prolif.2021549e1309910.1111/cpr.13099 34291515
     [Google Scholar]
  37. MengQ. ChengY. ZhouC. Pharmacokinetic interaction between rhynchopylline and pellodendrine via CYP450 enzymes and P-gp.Pharm. Biol.20215911549155310.1080/13880209.2021.1999988 34757861
     [Google Scholar]
  38. LamP.Y. KutchukianP. AnandR. Cyp1 inhibition prevents doxorubicin‐induced cardiomyopathy in a zebrafish heart‐failure model.ChemBioChem202021131905191010.1002/cbic.201900741 32003101
     [Google Scholar]
  39. DhulkifleH. TherachiyilL. HasanM.H. Inhibition of cytochrome P450 epoxygenase promotes endothelium-to-mesenchymal transition and exacerbates doxorubicin-induced cardiovascular toxicity.Mol. Biol. Rep.202451185910.1007/s11033‑024‑09803‑z 39066934
     [Google Scholar]
  40. SunB. YangY. HeM. Hepatoprotective role of berberine on doxorubicin induced hepatotoxicity - involvement of cyp.Curr. Drug Metab.202021754154710.2174/1389200221666200620203648 32586251
     [Google Scholar]
  41. KaurG. GuptaS.K. SinghP. AliV. KumarV. VermaM. Drug-metabolizing enzymes: Role in drug resistance in cancer.Clin. Transl. Oncol.202022101667168010.1007/s12094‑020‑02325‑7 32170639
     [Google Scholar]
  42. AsnaniA. ZhengB. LiuY. Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity.JCI Insight201831e9675310.1172/jci.insight.96753 29321375
     [Google Scholar]
  43. ArnoldW.R. DasA. An emerging pathway of doxorubicin cardiotoxicity mediated through CYP2J2.Biochemistry201857162294229610.1021/acs.biochem.8b00337 29629756
     [Google Scholar]
  44. SantosD.K.F. MaterónE.M. OliveiraO.N. Influence of cytochrome P450 3A4 and membrane lipid composition on doxorubicin activity.Colloids Surf. B Biointerfaces202222011288610.1016/j.colsurfb.2022.112886 36183636
     [Google Scholar]
  45. GrantM.K.O. AbdelgawadI.Y. LewisC.A. ZordokyB.N. Sexual dimorphism in doxorubicin-induced systemic inflammation: Implications for hepatic cytochrome p450 regulation.Int. J. Mol. Sci.2020214127910.3390/ijms21041279 32074957
     [Google Scholar]
  46. KabeY. NakaneT. KoikeI. Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance.Nat. Commun.2016711103010.1038/ncomms11030 26988023
     [Google Scholar]
  47. RosicG. Cancer signaling, cell/gene therapy, diagnosis and role of nanobiomaterials.20249Special Issue113410.62476/abes9s11
     [Google Scholar]
  48. KhalilovR BakishzadeA NasibovaA Future prospects of biomaterials in nanomedicine.Adv Biol Earth Sci20238Special Issu51010.62476/abes.9s5
     [Google Scholar]
  49. HuseynovE. KhalilovR. MohamedA.J. Novel nanomaterials for hepatobiliary diseases treatment and future perspectives.Adv Biol Earth Sci20249Special Issue819110.62476/abes9s81
     [Google Scholar]
  50. RodrigoL. GilF. HernandezA.F. LopezO. PlaA. Identification of paraoxonase 3 in rat liver microsomes: Purification and biochemical properties.Biochem. J.2003376126126810.1042/bj20030732 12946270
     [Google Scholar]
  51. LiL. ShiH. HuaX. WangM. WangH. Intrinsic clearance and metabolism pathway of fosthiazate in rat and cock liver microsomes: From chiral assessment view.J. Agric. Food Chem.20216943126541266010.1021/acs.jafc.1c05217 34695356
     [Google Scholar]
  52. PriceR.J. ScottM.P. CantrillC. Kinetics of metabolism of deltamethrin and cis - and trans -permethrin in vitro. Studies using rat and human liver microsomes, isolated rat hepatocytes and rat liver cytosol.Xenobiotica2021511405010.1080/00498254.2020.1807075 32757971
     [Google Scholar]
  53. KielkopfCL BauerW UrbatschIL Bradford assay for determining protein concentration.Cold Spring Harb Protoc202020204pdb.prot10226910.1101/pdb.prot10226932238597
     [Google Scholar]
  54. KielkopfCL BauerW UrbatschIL Methods for measuring the concentrations of proteins.Cold Spring Harb Protoc202020204pdb.top10227710.1101/pdb.top10227732238598
     [Google Scholar]
  55. WuS.A. ShenC. WeiX. The mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes.Nat. Commun.2023141313210.1038/s41467‑023‑38690‑4 37253728
     [Google Scholar]
  56. HeZ.H. ShaoL.Q. XuanL.Y. Effect of Astragalus injection on cardiomyocyte apoptosis, endoplasmic reticulum stress and expression of connexin in cardiomyopathy rats induced by adriamycin.Chung Kuo Ying Yung Sheng Li Hsueh Tsa Chih2018342159163 29926682
     [Google Scholar]
  57. ClarJ. GriB. CalderaroJ. Targeted deletion of kidney glucose-6 phosphatase leads to nephropathy.Kidney Int.201486474775610.1038/ki.2014.102 24717294
     [Google Scholar]
  58. LuoZ. LiuY. ZhaoZ. YanX. WangD. LiuQ. Effects of Astragalus injection and Salvia Miltiorrhiza injection on serum inflammatory markers in patients with stable coronary heart disease: A randomized controlled trial protocol.Trials202021126710.1186/s13063‑020‑4109‑6 32178701
     [Google Scholar]
  59. LiuK. WanG. JiangR. Astragalus injection ameliorates lipopolysaccharide-induced cognitive decline via relieving acute neuroinflammation and BBB damage and upregulating the BDNF-CREB pathway in mice.Pharm. Biol.202260182583910.1080/13880209.2022.2062005 35587259
     [Google Scholar]
  60. SunY. HeM. SunY. WeiJ. 4-O-galloylalbiflorin inhibits the activity of CYP3A, 2C9, and 2D in human liver microsomes.Xenobiotica202151887187610.1080/00498254.2021.1936688 34082641
     [Google Scholar]
  61. SchneiderD. BierD. BauerA. NeumaierB. HolschbachM. Influence of incubation conditions on microsomal metabolism of xanthine-derived A1 adenosine receptor ligands.J. Pharmacol. Toxicol. Methods201995162610.1016/j.vascn.2018.11.005 30476620
     [Google Scholar]
  62. ZhuL.J. SunS.S. HuY.X. LiuY.F. Metabolism studies of paeoniflorin in rat liver microsomes by ultra-performance liquid chromatography coupled with hybrid quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS).R. Soc. Open Sci.201851018075910.1098/rsos.180759 30473826
     [Google Scholar]
  63. HakkolaJ. HukkanenJ. TurpeinenM. PelkonenO. Inhibition and induction of CYP enzymes in humans: An update.Arch. Toxicol.202094113671372210.1007/s00204‑020‑02936‑7 33111191
     [Google Scholar]
  64. Saiz-RodríguezM. OchoaD. BelmonteC. Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics.J. Psychopharmacol.201933452253110.1177/0269881119827959 30789308
     [Google Scholar]
  65. YuJ. XiaX. DongY. CYP1A2 suppresses hepatocellular carcinoma through antagonizing HGF/MET signaling.Theranostics20211152123213610.7150/thno.49368 33500715
     [Google Scholar]
  66. HolbrookA.M. PereiraJ.A. LabirisR. Systematic overview of warfarin and its drug and food interactions.Arch. Intern. Med.2005165101095110610.1001/archinte.165.10.1095 15911722
     [Google Scholar]
  67. BocciaS. MieleL. PanicN. The effect of CYP, GST, and SULT polymorphisms and their interaction with smoking on the risk of hepatocellular carcinoma.BioMed Res. Int.201520151710.1155/2015/179867 25654087
     [Google Scholar]
  68. GaoJ. WangZ. WangG.J. Higher CYP2E1 activity correlates with hepatocarcinogenesis induced by diethylnitrosamine.J. Pharmacol. Exp. Ther.2018365239840710.1124/jpet.117.245555 29467309
     [Google Scholar]
  69. YinX. XiongW. WangY. Association of CYP2E1 gene polymorphisms with bladder cancer risk.Medicine20189739e1191010.1097/MD.0000000000011910 30278485
     [Google Scholar]
  70. GuengerichF.P. Cytochrome P450 2E1 and its roles in disease.Chem. Biol. Interact.202032210905610.1016/j.cbi.2020.109056 32198084
     [Google Scholar]
  71. LuY. WangY. HeY. Aidi injection altered the activity of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 in normal and diethylnitrosamine-induced hepatocellular carcinoma in rats.J. Ethnopharmacol.202228611493010.1016/j.jep.2021.114930 34952190
     [Google Scholar]
  72. KianiY.S. RanaghanK.E. JabeenI. MulhollandA.J. Molecular dynamics simulation framework to probe the binding hypothesis of CYP3A4 inhibitors.Int. J. Mol. Sci.20192018446810.3390/ijms20184468 31510073
     [Google Scholar]
  73. HuY. QuanZ. LiD. WangC. SunZ. Inhibition of CYP3A4 enhances aloe-emodin induced hepatocyte injury.Toxicol. In Vitro20227910527610.1016/j.tiv.2021.105276 34875353
     [Google Scholar]
  74. liuQ Ou-YangQG LinQM Effects of 27 CYP3A4 protein variants on saxagliptin metabolism in vitro.Fundam Clin Pharmacol2022361150910.1111/fcp.1269333961299
     [Google Scholar]
  75. ZangerU.M. SchwabM. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation.Pharmacol. Ther.2013138110314110.1016/j.pharmthera.2012.12.007 23333322
     [Google Scholar]
  76. MoS.L. LiuY.H. DuanW. WeiM. KanwarJ. ZhouS.F. Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6.Curr. Drug Metab.200910773075310.2174/138920009789895534 19702527
     [Google Scholar]
/content/journals/cpd/10.2174/0113816128362829250527023843
Loading
Astragalus Injection Modulates the Pharmacokinetics of Doxorubicin and CYP450 Enzymes
Curr. Pharm. Des. 31, 3234 (2025); https://doi.org/10.2174/0113816128362829250527023843
/content/journals/cpd/10.2174/0113816128362829250527023843
/content/journals/cpd/10.2174/0113816128362829250527023843
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): Astragali radix; CYP1A2; CYP3A4; drug resistance; Drug-drug interaction; metabolism

Most Cited Most Cited RSS feed

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