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Influence of Nutritional Status on the Absorption of Polyphyllin I, an Anticancer Candidate from Paris polyphylla in Rats

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Protein–calorie malnutrition (PCM) is one of the most suffered complications in cancer patients. Polyphyllin I (PPI), a saponin isolated from rhizome of Paris polyphylla, is a potential candidate in cancer therapy. In this study, the influence of nutritional status on the absorption of PPI in rats was explored after oral administration.

Methods

PCM rats, namely mal-nourished (MN) rats, were induced from well-nourished (WN) rats by caloric restriction protocol. Intestinal absorption of PPI in WN and MN rats was evaluated by pharmacokinetic and intestinal perfusion methods. The potential mechanisms between two groups were investigated on the basis of intestinal permeability, intestinal efflux and PPI’s depletions in vivo. The intestinal permeability was analyzed by determining the concentration of paracellular marker transport in serum and the expression of junction proteins in intestine. The intestinal efflux was evaluated through comparing the protein level of P-glycoprotein (P-gp) in intestine, and the depletions of PPI and/or generation of its metabolites in liver and intestines were analyzed by liquid chromatography triple quadrupole mass spectrometry (LC–MS/MS) method.

Results

Compared to WN rats, the oral systemic exposure of PPI was significantly increased in MN rats, evidenced by significant enhancement of maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC0–60h) by more than 2.51- and 3.71-folds as well as terminal elimination half-life (t1/2) prolonged from to 7.3 to 14.1 h. Further studies revealed that the potential mechanism might be associated with combined contribution of improved intestinal absorption and depressed deglycosylation of PPI in MN rats. Furthermore, enhanced intestinal absorption of PPI was benefited from increased intestinal permeability and decreased intestinal efflux in MN rats. Meanwhile, the former manifested as increased transport of paracellular marker and decreased junction proteins levels, while the later evidenced by reduced P-gp expression.

Conclusions

The oral exposure of PPI was enhanced in MN rats, which suggested that nutritional status alters the absorption of PPI, and thus the dosage of PPI should be modified during the treatment of cancer patient with PCM.

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References

  1. Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–93. https://doi.org/10.3322/caac.21395.

    Article  PubMed  Google Scholar 

  2. Ethun CG, Bilen MA, Jani AB, Maithel SK, Ogan K, Master VA. Frailty and cancer: implications for oncology surgery, medical oncology, and radiation oncology. CA Cancer J Clin. 2017;67(5):362–77. https://doi.org/10.3322/caac.21406.

    Article  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. https://doi.org/10.3322/caac.21442.

    Article  PubMed  Google Scholar 

  4. Gangadharan A, Choi SE, Hassan A, Ayoub NM, Durante G, Balwani S, et al. Protein calorie malnutrition, nutritional intervention and personalized cancer care. Oncotarget. 2017;8(14):24009–30. https://doi.org/10.18632/oncotarget.15103.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Nitenberg G, Raynard B. Nutritional support of the cancer patient: issues and dilemmas. Crit Rev Oncol Hematol. 2000;34(3):137–68.

    Article  PubMed  CAS  Google Scholar 

  6. Perez-Pitarch A, Guglieri-Lopez B, Nacher A, Merino V, Merino-Sanjuan M. Impact of undernutrition on the pharmacokinetics and pharmacodynamics of anticancer drugs: a literature review. Nutr Cancer. 2017;69(4):555–63. https://doi.org/10.1080/01635581.2017.1299878.

    Article  PubMed  Google Scholar 

  7. Chen Y, Zhu J, Zhang W. Antitumor effect of traditional Chinese herbal medicines against lung cancer. Anticancer Drugs. 2014;25(9):983–91. https://doi.org/10.1097/CAD.0000000000000127.

    Article  PubMed  CAS  Google Scholar 

  8. Li L, Wu J, Zheng F, Tang Q, Wu W, Hann SS. Inhibition of EZH2 via activation of SAPK/JNK and reduction of p65 and DNMT1 as a novel mechanism in inhibition of human lung cancer cells by polyphyllin I. J Exp Clin Cancer Res. 2016;35(1):112. https://doi.org/10.1186/s13046-016-0388-x.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Ong RC, Lei J, Lee RK, Cheung JY, Fung KP, Lin C, et al. Polyphyllin D induces mitochondrial fragmentation and acts directly on the mitochondria to induce apoptosis in drug-resistant HepG2 cells. Cancer Lett. 2008;261(2):158–64. https://doi.org/10.1016/j.canlet.2007.11.005.

    Article  PubMed  CAS  Google Scholar 

  10. Shi YM, Yang L, Geng YD, Zhang C, Kong LY. Polyphyllin I induced-apoptosis is enhanced by inhibition of autophagy in human hepatocellular carcinoma cells. Phytomedicine. 2015;22(13):1139–49. https://doi.org/10.1016/j.phymed.2015.08.014.

    Article  PubMed  CAS  Google Scholar 

  11. Chan JY, Koon JC, Liu X, Detmar M, Yu B, Kong SK, et al. Polyphyllin D, a steroidal saponin from Paris polyphylla, inhibits endothelial cell functions in vitro and angiogenesis in zebrafish embryos in vivo. J Ethnopharmacol. 2011;137(1):64–9. https://doi.org/10.1016/j.jep.2011.04.021.

    Article  PubMed  CAS  Google Scholar 

  12. Chang J, Li Y, Wang X, Hu S, Wang H, Shi Q, et al. Polyphyllin I suppresses human osteosarcoma growth by inactivation of Wnt/beta-catenin pathway in vitro and in vivo. Sci Rep. 2017;7(1):7605. https://doi.org/10.1038/s41598-017-07194-9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Chang J, Wang H, Wang X, Zhao Y, Zhao D, Wang C, et al. Molecular mechanisms of Polyphyllin I-induced apoptosis and reversal of the epithelial-mesenchymal transition in human osteosarcoma cells. J Ethnopharmacol. 2015;170:117–27. https://doi.org/10.1016/j.jep.2015.05.006.

    Article  PubMed  CAS  Google Scholar 

  14. Li ZH, Zhu H, Cai XP, He DD, Hua JL, Ju JM, et al. Simultaneous determination of five triterpene acids in rat plasma by liquid chromatography-mass spectrometry and its application in pharmacokinetic study after oral administration of Folium Eriobotryae effective fraction. Biomed Chromatogr. 2015;29(12):1791–7. https://doi.org/10.1002/bmc.3497.

    Article  PubMed  CAS  Google Scholar 

  15. Shakya S, Zhu H, Ding L, Du XL, Qi XM, Yang XL, et al. Determination of asperosaponin VI in dog plasma by high-performance liquid chromatography-tandem mass spectrometry and its application to a pilot pharmacokinetic study. Biomed Chromatogr. 2012;26(1):109–14. https://doi.org/10.1002/bmc.1634.

    Article  PubMed  CAS  Google Scholar 

  16. Zhu H, Ding L, Shakya S, Qi X, Hu L, Yang X, et al. Simultaneous determination of asperosaponin VI and its active metabolite hederagenin in rat plasma by liquid chromatography-tandem mass spectrometry with positive/negative ion-switching electrospray ionization and its application in pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2011;879(30):3407–14. https://doi.org/10.1016/j.jchromb.2011.09.014.

    Article  PubMed  CAS  Google Scholar 

  17. Zhu H, Zhu SC, Shakya S, Mao Q, Ding CH, Long MH, et al. Study on the pharmacokinetics profiles of polyphyllin I and its bioavailability enhancement through co-administration with P-glycoprotein inhibitors by LC–MS/MS method. J Pharm Biomed Anal. 2015;107:119–24. https://doi.org/10.1016/j.jpba.2014.12.002.

    Article  PubMed  CAS  Google Scholar 

  18. Liu YC, Zhu H, Shakya S, Wu JW. Metabolic profile and pharmacokinetics of polyphyllin I, an anticancer candidate, in rats by UPLC-QTOF-MS/MS and LC-TQ-MS/MS. Biomed Chromatogr. 2017;31(3). https://doi.org/10.1002/bmc.3817.

  19. Liu C, Hu M, Guo H, Zhang M, Zhang J, Li F, et al. Combined contribution of increased intestinal permeability and inhibited deglycosylation of ginsenoside Rb1 in the intestinal tract to the enhancement of ginsenoside Rb1 exposure in diabetic rats after oral administration. Drug Metab Dispos. 2015;43(11):1702–10. https://doi.org/10.1124/dmd.115.064881.

    Article  PubMed  CAS  Google Scholar 

  20. Yang Z, Gao S, Wang J, Yin T, Teng Y, Wu B, et al. Enhancement of oral bioavailability of 20(S)-ginsenoside Rh2 through improved understanding of its absorption and efflux mechanisms. Drug Metab Dispos. 2011;39(10):1866–72. https://doi.org/10.1124/dmd.111.040006.

    Article  PubMed  CAS  Google Scholar 

  21. Zhou J, Ma YH, Zhou Z, Chen Y, Wang Y, Gao X. Intestinal absorption and metabolism of epimedium flavonoids in osteoporosis rats. Drug Metab Dispos. 2015;43(10):1590–600. https://doi.org/10.1124/dmd.115.064386.

    Article  PubMed  CAS  Google Scholar 

  22. Adebayo OL, Adenuga GA, Sandhir R. Selenium and zinc protect brain mitochondrial antioxidants and electron transport chain enzymes following postnatal protein malnutrition. Life Sci. 2016;152:145–55. https://doi.org/10.1016/j.lfs.2016.03.008.

    Article  PubMed  CAS  Google Scholar 

  23. Perez-Garcia G, Guzman-Quevedo O, Da Silva Aragao R, Bolanos-Jimenez F. Early malnutrition results in long-lasting impairments in pattern-separation for overlapping novel object and novel location memories and reduced hippocampal neurogenesis. Sci Rep. 2016;6:21275. https://doi.org/10.1038/srep21275.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Nevado R, Forcen R, Layunta E, Murillo MD, Grasa L. Neomycin and bacitracin reduce the intestinal permeability in mice and increase the expression of some tight-junction proteins. Rev Esp Enferm Dig. 2015;107(11):672–6. https://doi.org/10.17235/reed.2015.3868/2015.

    Article  PubMed  CAS  Google Scholar 

  25. Furge LL, Guengerich FP. Cytochrome P450 enzymes in drug metabolism and chemical toxicology: an introduction. Biochem Mol Biol Educ. 2006;34(2):66–74. https://doi.org/10.1002/bmb.2006.49403402066.

    Article  PubMed  CAS  Google Scholar 

  26. Choi YH, Yoon I, Kim YG, Lee MG. Effects of cysteine on the pharmacokinetics of docetaxel in rats with protein-calorie malnutrition. Xenobiotica. 2012;42(5):442–55. https://doi.org/10.3109/00498254.2011.629376.

    Article  PubMed  CAS  Google Scholar 

  27. Perez-Pitarch A, Nacher A, Merino V, Catalan-Latorre A, Jimenez-Torres NV, Merino-Sanjuan M. Impact of nutritional status on the pharmacokinetics of erlotinib in rats. Biopharm Drug Dispos. 2015. https://doi.org/10.1002/bdd.1948.

    Article  PubMed  Google Scholar 

  28. El-Demerdash E, Ali AA, El-Taher DE, Hamada FM. Effect of low-protein diet on anthracycline pharmacokinetics and cardiotoxicity. J Pharm Pharmacol. 2012;64(3):344–52. https://doi.org/10.1111/j.2042-7158.2011.01413.x.

    Article  PubMed  CAS  Google Scholar 

  29. Lee YK, Yoon I, Lee MG, Choi YH. Effects of cysteine on the pharmacokinetics of tamoxifen in rats with protein-calorie malnutrition. Xenobiotica. 2012;42(12):1225–34. https://doi.org/10.3109/00498254.2012.683498.

    Article  PubMed  CAS  Google Scholar 

  30. Gandhi A, Moorthy B, Ghose R. Drug disposition in pathophysiological conditions. Curr Drug Metab. 2012;13(9):1327–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Tran TH, Smith C, Mangione RA. Drug absorption in celiac disease. Am J Health Syst Pharm. 2013;70(24):2199–206. https://doi.org/10.2146/ajhp120689.

    Article  PubMed  CAS  Google Scholar 

  32. Yang Z, Wang JR, Niu T, Gao S, Yin T, You M, et al. Inhibition of P-glycoprotein leads to improved oral bioavailability of compound K, an anticancer metabolite of red ginseng extract produced by gut microflora. Drug Metab Dispos. 2012;40(8):1538–44. https://doi.org/10.1124/dmd.111.044008.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Ferraris RP, Carey HV. Intestinal transport during fasting and malnutrition. Annu Rev Nutr. 2000;20:195–219. https://doi.org/10.1146/annurev.nutr.20.1.195.

    Article  PubMed  CAS  Google Scholar 

  34. Ahn CY, Kim EJ, Kwon JW, Chung SJ, Kim SG, Shim CK, et al. Effects of cysteine on the pharmacokinetics of intravenous clarithromycin in rats with protein-calorie malnutrition. Life Sci. 2003;73(14):1783–94.

    Article  PubMed  CAS  Google Scholar 

  35. Qin ZF, Dai Y, Yao ZH, He LL, Wang QY, Geng JL, et al. Study on chemical profiles and metabolites of Allii Macrostemonis Bulbus as well as its representative steroidal saponins in rats by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Food Chem. 2016;192:499–515. https://doi.org/10.1016/j.foodchem.2015.07.040.

    Article  PubMed  CAS  Google Scholar 

  36. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971–6. https://doi.org/10.1126/science.1240537.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Tilg H, Moschen AR. Malnutrition and microbiota—a new relationship? Nat Rev Gastroenterol Hepatol. 2013;10(5):261–2. https://doi.org/10.1038/nrgastro.2013.48.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Linyi Central Hospital, Linyi, 276400, People’s Republic of China

    Feng-Ling Yu, Wei-Liang Gong & Fang-Jiang Xu

  2. Department of Pharmaceutical Analysis and Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine and Jiangsu Branch of China Academy of Chinese Medical Sciences, Shizi Street No. 100, Hongshan Road, Nanjing, 210028, People’s Republic of China

    Jun-Wen Wu & He Zhu

  3. Department of Pharmacy, School of Science, Kathmandu University, Dhulikhel, Kavre, 45210, Nepal

    Shailendra Shakya

  4. Novo Trial SMO Co., Ltd, Beijing, 100124, People’s Republic of China

    Jun-Wen Wu

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  1. Feng-Ling Yu
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Corresponding authors

Correspondence to Shailendra Shakya or He Zhu.

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Funding

This study was financially supported by National Natural Science Foundation of China (no. 81503365) and Natural Science Foundation of Jiangsu Province, China (no. BK20151050).

Conflicts of interest

The authors declare no conflict of interest.

Ethics approval

The study was approved by the Animal Ethics Committee of Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, P.R. China.

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Yu, FL., Gong, WL., Xu, FJ. et al. Influence of Nutritional Status on the Absorption of Polyphyllin I, an Anticancer Candidate from Paris polyphylla in Rats. Eur J Drug Metab Pharmacokinet 43, 587–597 (2018). https://doi.org/10.1007/s13318-018-0473-y

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