Skip to main content
SpringerLink
Log in

Intestinal Absorption of Isoalantolactone and Alantolactone, Two Sesquiterpene Lactones from Radix Inulae, Using Caco-2 Cells

  • Short Communication
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background

Isoalantolactone and alantolactone are the main sesquiterpene lactones in Radix Inulae (dried root of Inula helenium L. or I. racemosa Hook. F.), which is a frequently utilized herbal medicine. They also occur in several plants and have various pharmacologic effects. However, they have been found to have poor oral bioavailability in rats.

Objectives

To understand the intestinal absorptive characteristics of isoalantolactone and alantolactone as well specific influx and efflux transporters in their absorption.

Methods

Bidirectional permeabilities of isoalantolactone and alantolactone were investigated across Caco-2 cell monolayers. Transport assays were performed using different concentrations of two lactones and specific inhibitors of ATP-binding cassette transporters and influx transporters.

Results

The absorption permeability of isoalantolactone and alantolactone was high at the tested concentrations (5, 20 and 80 μmol/l), and the major permeation mechanism of both lactones was found to be passive diffusion with active efflux mediated by multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP).

Conclusion

Our results demonstrated that the absorption permeability of isoalantolactone and alantolactone was good in the Caco-2 cell model. The isoalantolactone and alantolactone absorption elucidated in this study provides useful information for further pharmacokinetics studies. Since low intestinal absorption can now be ruled out as a cause, further studies are needed to explain the low oral bioavailability of the two sesquiterpene lactones.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

References

  1. Bohlmann F, Mahanta PK, Jakupovic J, Rastogi RC, Natu AA. New sesquiterpene lactones from Inula species. Phytochemistry. 1978;17(7):1165–72.

    Article  CAS  Google Scholar 

  2. Stojakowska A, Michalska K, Malarz J. Simultaneous quantification of eudesmanolides and thymol derivatives from tissues of Inula helenium and I. royleana by reversed-phase high-performance liquid chromatography. Phytochem Anal. 2006;17(3):157–61.

    Article  CAS  PubMed  Google Scholar 

  3. Editorial Board of Jiangsu New Hospital. The dictionary of traditional medicine. Shanghai: Shanghai Scientific & Technical Press; 1985. p. 80–82.

    Google Scholar 

  4. Huo Y, Shi HM, Li WW, Li XB. HPLC determination and NMR structural elucidation of sesquiterpene lactones in Inula helenium. J Pharm Biomed Anal. 2010;51(4):942–6.

    Article  CAS  PubMed  Google Scholar 

  5. Peng Y, Wang SQ, Wang MY, Wang F, Yang JY, Wu CF, Li XB. Dual effects on constipation and diarrhea: protective potential of Radix Inulae lactones on irritable bowel syndrome. RSC Adv. 2016;6:94486–95.

    Article  CAS  Google Scholar 

  6. Schmidt TJ, Brun R, Willuhn G, Khalid SA. Anti-trypanosomal activity of helenalin and some structurally related sesquiterpene lactones. Planta Med. 2002;68(8):750–1.

    Article  CAS  PubMed  Google Scholar 

  7. Qiu J, Luo M, Wang J, Dong J, Li H, Leng B, Zhang Q, Dai X, Zhang Y, Niu X, Deng X. Isoalantolactone protects against Staphylococcus aureus pneumonia. FEMS Microbiol Lett. 2011;324(2):147–55.

    Article  CAS  PubMed  Google Scholar 

  8. Stojanović-Radić Z, Čomić L, Radulović N, Blagojević P, Denić M, Miltojević A, Rajković J, Mihajilov-Krstev T. Antistaphylococcal activity of Inula helenium L. root essential oil: eudesmane sesquiterpene lactones induce cell membrane damage. Eur J Clin Microbiol Infect Dis. 2012;31(6):1015–25.

    Article  CAS  PubMed  Google Scholar 

  9. Chun J, Choi RJ, Khan S, Lee DS, Kim YC, Nam YJ, Lee DU, Kim YS. Alantolactone suppresses inducible nitric oxide synthase and cyclooxygenase-2 expression by down-regulating NF-κB, MAPK and AP-1 via the MyD88 signaling pathway in LPS-activated RAW 264.7 cells. Int Immunopharmacol. 2012;14(4):375–83.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang Y, Bao YL, Wu Y, Yu CL, Huang YX, Sun Y, Zheng LH, Li YX. Alantolactone induces apoptosis in RKO cells through the generation of reactive oxygen species and the mitochondrial pathway. Mol Med Rep. 2013;8(4):967–72.

    Article  CAS  PubMed  Google Scholar 

  11. Chun J, Li R, Cheng M, Kim YS. Alantolactone selectively suppresses STAT3 activation and exhibits potent anticancer activity in MDA-MB-231 cells. Cancer Lett. 2015;357(1):393–403.

    Article  CAS  PubMed  Google Scholar 

  12. Zhao P, Pan Z, Luo Y, Zhang L, Li X, Zhang G, Zhang Y, Cui R, Sun M, Zhang X. Alantolactone induces apoptosis and cell cycle arrest on lung squamous cancer SK-MES-1 cells. J Biochem Mol Toxicol. 2015;29(5):199–206.

    Article  CAS  PubMed  Google Scholar 

  13. Cai H, Meng X, Li Y, Yang C, Liu Y. Growth inhibition effects of isoalantolactone on K562/A02 cells: caspase-dependent apoptotic pathways, S phase arrest, and downregulation of Bcr/Abl. Phytother Res. 2014;28(11):1679–86.

    Article  CAS  PubMed  Google Scholar 

  14. Rasul A, Khan M, Yu B, Ali M, Bo YJ, Yang H, Ma T. Isoalantolactone, a sesquiterpene lactone, induces apoptosis in SGC-7901 cells via mitochondrial and phosphatidylinositol 3-kinase/Akt signaling pathways. Arch Pharm Res. 2013;36(10):1262–9.

    Article  CAS  PubMed  Google Scholar 

  15. Xu RJ, Zhou GS, Peng Y, Wang MY, Li XB. Pharmacokinetics, tissue distribution and excretion of isoalantolactone and alantolactone in rats after oral administration of Radix Inulae extract. Molecules. 2015;20(5):7719–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Guo C, Zhang S, Teng S, Niu K. Simultaneous determination of sesquiterpene lactones isoalantolactone and alantolactone isomers in rat plasma by liquid chromatography with tandem mass spectrometry: application to a pharmacokinetic study. J Sep Sci. 2014;37(8):950–6.

    Article  CAS  PubMed  Google Scholar 

  17. Xu RJ, Wang MY, Peng Y, Li XB. Pharmacokinetic comparison of isoalantolactone and alantolactone in rats after administration separately by optimization of an UPLC-MS2 method. J Chem. 2014;2014:354618.

    Google Scholar 

  18. Amorim MH, Gil da Costa RM, Lopes C, Bastos MM. Sesquiterpene lactones: adverse health effects and toxicity mechanisms. Crit Rev Toxicol. 2013;43(7):559–79.

    Article  CAS  PubMed  Google Scholar 

  19. Zhu M, Liang X, Zhao L, Liao ZG, Zhao GW, Cao YC, Zhang J, Luo Y. Elucidation of the transport mechanism of baicalin and the influence of a Radix Angelicae dahuricae extract on the absorption of baicalin in a Caco-2 cell monolayer model. J Ethnopharmacol. 2013;150(2):553–9.

    Article  CAS  PubMed  Google Scholar 

  20. Hidalgo IJ, Raub TJ, Borchardt RT. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology. 1989;96(3):736–49.

    Article  CAS  PubMed  Google Scholar 

  21. Duan J, Xie Y, Luo H, Li G, Wu T, Zhang T. Transport characteristics of isorhamnetin across intestinal Caco-2 cell monolayers and the effects of transporters on it. Food Chem Toxicol. 2014;66:313–20.

    Article  CAS  PubMed  Google Scholar 

  22. Kuwayama K, Inoue H, Kanamori T, Tsujikawa K, Miyaguchi H, Iwata Y, Miyauchi S, Kamo N, Kishi T. Uptake of 3,4-methylenedioxymethamphetamine and its related compounds by a proton-coupled transport system in Caco-2 cells. Biochim Biophys Acta. 2008;1778(1):42–50.

    Article  CAS  PubMed  Google Scholar 

  23. Crowe A, Diep S. pH dependent efflux of methamphetamine derivatives and their reversal through human Caco-2 cell monolayers. Eur J Pharmacol. 2008;592:7–12.

    Article  CAS  PubMed  Google Scholar 

  24. Chen Y, Wang Y, Zhou J, Gao X, Qu D, Liu C. Study on the mechanism of intestinal absorption of epimedins A, B and C in the Caco-2 cell model. Molecules. 2014;19(1):686–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Guo J, Yang X. Intestinal permeability of atractylenolides across the human Caco-2 cell monolayer model. J Chin Pharm Sci. 2011;20(5):505–9.

    Article  CAS  Google Scholar 

  26. Zhang B, Zhu X, Hu J, Ye H, Luo T, Liu XR, Li HY, Li W, Zheng YN, Deng ZY. Absorption mechanism of Ginsenoside compound K and its butyl and octyl ester prodrugs in Caco-2 cells. J Agric Food Chem. 2012;60(41):10278–84.

    Article  CAS  PubMed  Google Scholar 

  27. Uršič D, Berginc K, žakelj S, Kristl A. Influence of luminal monosaccharides on secretion of glutathione conjugates from rat small intestine in vitro. Int J Pharm. 2009;381(2):199–204.

    Article  CAS  PubMed  Google Scholar 

  28. Prime-Chapman HM, Fearn RA, Cooper AE, Moore V, Hirst BH. Differential multidrug resistance-associated protein 1 through 6 isoform expression and function in human intestinal epithelial Caco-2 cells. J Pharmacol Exp Ther. 2004;311(2):476–84.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang L, Lin G, Kovács B, Jani M, Krajcsi P, Zuo Z. Mechanistic study on the intestinal absorption and disposition of baicalein. Eur J Pharm Sci. 2007;31:221–31.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang S, Yang X, Morris ME. Combined effects of multiple flavonoids on breast cancer resistance protein (ABCG2)-mediated transport. Pharm Res. 2004;21(7):1263–73.

    Article  CAS  PubMed  Google Scholar 

  31. Chabane MN, Ahmad AA, Peluso J, Muller CD, Ubeaud GJ. Quercetin and naringenin transport across human intestinal Caco-2 cells. J Pharm Pharmacol. 2009;61(11):1473–83.

    Article  CAS  Google Scholar 

  32. Wahlang B, Pawar YB, Bansal AK. Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell model. Eur J Pharm Biopharm. 2011;77(2):275–82.

    Article  CAS  PubMed  Google Scholar 

  33. Yee S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man–fact or myth. Pharm Res. 1997;14(6):763–6.

    Article  CAS  PubMed  Google Scholar 

  34. Harris RZ, Jang GR, Tsunoda S. Dietary effects on drug metabolism and transport. Clin Pharmacokinet. 2003;42(13):1071–88.

    Article  CAS  PubMed  Google Scholar 

  35. Laitinen L, Takala E, Vuorela H, Vuorela P, Kaukonen AM, Marvola M. Anthranoid laxatives influence the absorption of poorly permeable drugs in human intestinal cell culture model (Caco-2). Eur J Pharm Biopharm. 2007;66:135–45.

    Article  CAS  PubMed  Google Scholar 

  36. Müller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol. 2005;70(12):1851–60.

    Article  CAS  PubMed  Google Scholar 

  37. Jonker JW, Schinkel AH. Pharmacological and physiological functions of the polyspecific organic cation transporters OCT1, 2, and 3 (SLC22A1-3). J Pharmacol Exp Ther. 2004;308:2–9.

    Article  CAS  PubMed  Google Scholar 

  38. Estudante M, Morais JG, Soveral G, Benet LZ. Intestinal drug transporters: an overview. Adv Drug Deliv Rev. 2013;65(10):1340–56.

    Article  CAS  PubMed  Google Scholar 

  39. Liu ZH, Liu KX. The transporters of intestinal tract and techniques applied to evaluate interactions between drugs and transporters. Asian J Pharm Sci. 2013;8(3):151–8.

    Article  CAS  Google Scholar 

  40. Bansal T, Jaggi M, Khar RK. Emerging significance of flavonoids as P-glycoprotein inhibitors in cancer chemotherapy. J Pharm Pharm Sci. 2009;12(1):46–78.

    Article  CAS  PubMed  Google Scholar 

  41. Bromberg L, Alakhov V. Effects of polyether-modified poly (acrylic acid) microgels on doxorubicin transport in human intestinal epithelial Caco-2 cell layers. J Control Release. 2003;88(1):11–22.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Renjie Xu and Ying Peng contributed to this paper equally.

Authors and Affiliations

  1. School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Road, Minhang District, Shanghai, 200240, People’s Republic of China

    Renjie Xu, Ying Peng, Mengyue Wang & Xiaobo Li

Authors
  1. Renjie Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mengyue Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaobo Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaobo Li.

Ethics declarations

Funding

This work was supported by the National Science & Technology Key Projects funded by the Chinese Government (2012ZX09103201-038).

Conflict of Interest

All the authors have no conficts of interest to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, R., Peng, Y., Wang, M. et al. Intestinal Absorption of Isoalantolactone and Alantolactone, Two Sesquiterpene Lactones from Radix Inulae, Using Caco-2 Cells. Eur J Drug Metab Pharmacokinet 44, 295–303 (2019). https://doi.org/10.1007/s13318-018-0510-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-018-0510-x

Search

Navigation