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Planta Med 2014; 80(04): 290-296
DOI: 10.1055/s-0033-1360334
Pharmacokinetic Investigations
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Ginsenoside Metabolites Inhibit P-Glycoprotein In Vitro and In Situ Using Three Absorption Models

Na Li
1   Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
2   University of Chinese Academy of Sciences, Beijing, China
,
Dandan Wang
1   Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
2   University of Chinese Academy of Sciences, Beijing, China
,
Guangbo Ge
1   Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
,
Xiuli Wang
3   Dalian Medical University, Dalian, China
,
Yong Liu
1   Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
,
Ling Yang
1   Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
› Author Affiliations
Further Information

Publication History

received 15 August 2013
revised 05 December 2013

accepted 05 January 2014

Publication Date:
03 February 2014 (online)

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Abstract

P-glycoprotein, an ATP-dependent transporter expressed in the gastrointestinal tract and tumor cells, mediates the efflux transport of multiple drugs. Inhibition or induction of P-glycoprotein by herbal ingredients can lead to herb-drug interactions and thus influence the activities of P-glycoprotein substrate drugs. The present study aimed to explore the effect of nine naturally occurring ginsenosides and their intestinal bacterial metabolites on P-glycoprotein-mediated transport. The results showed that three ginsenoside metabolites (CK, Ppd, and Ppt) formed by intestinal bacteria significantly enhanced rhodamine 123 retention in Caco-2 cells, increased the absorptive permeability of rhodamine 123, and decreased the efflux ratio of digoxin in two absorption models, which were comparable to the effects of the known P-glycoprotein inhibitor verapamil. However, the prototype ginsenosides such as Rb1, Rb2, and Re showed no inhibitory effect on P-glycoprotein activity. In situ intestinal perfusion experiments also showed that CK, Ppd, and Ppt increased the absorption rate constant and permeability coefficient of rhodamine 123. Long-term treatment with CK, Ppd, and Ppt had no effect on P-glycoprotein mRNA expression in Caco-2 cells. In conclusion, CK, Ppd, and Ppt are potent P-glycoprotein inhibitors, indicating an unpredictable herb-drug interaction when ginsenosides are coadministered orally with P-glycoprotein substrate drugs.

Key words

ginseng - ginsenoside - intestinal metabolism - P-glycoprotein - inhibitor
 

  • References

  • 1 Marchetti S, Mazzanti R, Beijnen JH, Schellens JHM. Concise review: Clinical relevance of drug-drug and herb-drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). Oncologist 2007; 12: 927-941
    CrossrefPubMedSearch in Google Scholar
  • 2 Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KLR, Chu XY, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L. International Transporter Consortium. Membrane transporters in drug development. Nat Rev Drug Discov 2010; 9: 215-236
    CrossrefPubMedSearch in Google Scholar
  • 3 Shugarts S, Benet LZ. The role of transporters in the pharmacokinetics of orally administered drugs. Pharm Res 2009; 26: 2039-2054
    CrossrefPubMedSearch in Google Scholar
  • 4 Shitara Y, Horie T, Sugiyama Y. Transporters as a determinant of drug clearance and tissue distribution. Eur J Pharm Sci 2006; 27: 425-446
    CrossrefPubMedSearch in Google Scholar
  • 5 Clarke G, OʼMahony SM, Cryan JF, Dinan TG. Verapamil in treatment resistant depression: a role for the P-glycoprotein transporter?. Hum Psychopharmacol 2009; 24: 217-223
    PubMedSearch in Google Scholar
  • 6 Pitchakarn P, Ohnuma S, Pintha K, Pompimon W, Ambudkar SV, Limtrakul P. Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance. J Nutr Biochem 2012; 23: 76-84
    CrossrefPubMedSearch in Google Scholar
  • 7 Sukhaphirom N, Vardhanabhuti N, Chirdchupunseree H, Pramyothin P, Jianmongkol S. Phyllanthin and hypophyllanthin inhibit function of P-gp but not MRP2 in Caco-2 cells. J Pharm Pharmacol 2013; 65: 292-299
    CrossrefPubMedSearch in Google Scholar
  • 8 Qiangrong P, Wang T, Lu QH, Hu X. Schisandrin B–a novel inhibitor of P-glycoprotein. Biochem Biophys Res Commun 2005; 335: 406-411
    CrossrefPubMedSearch in Google Scholar
  • 9 Fu LW, Zhang YM, Liang YJ, Yang XP, Pan QC. The multidrug resistance of tumour cells was reversed by tetrandrine in vitro and in xenografts derived from human breast adenocarcinorna MCF-7/adr cells. Eur J Cancer 2002; 38: 418-426
    CrossrefPubMedSearch in Google Scholar
  • 10 Li N, Tsao R, Sui ZG, Ma JW, Liu ZQ, Liu ZY. Intestinal transport of pure diester-type alkaloids from an aconite extract across the Caco-2 cell monolayer model. Planta Med 2012; 78: 692-697
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Tsutsumi YM, Tsutsumi R, Mawatari K, Nakaya Y, Kinoshita M, Tanaka K, Oshita S. Compound K, a metabolite of ginsenosides, induces cardiac protection mediated nitric oxide via Akt/PI3K pathway. Life Sci 2011; 88: 725-729
    CrossrefPubMedSearch in Google Scholar
  • 12 Zhang B, Zhu XM, Hu JN, 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: 10278-10284
    CrossrefPubMedSearch in Google Scholar
  • 13 Liu X, Qiao LR, Xie D, Zhang Y, Zou JH, Chen XG, Dai JG. Microbial transformation of ginsenoside-Rg(1) by Absidia coerulea and the reversal activity of the metabolites towards multi-drug resistant tumor cells. Fitoterapia 2011; 82: 1313-1317
    CrossrefPubMedSearch in Google Scholar
  • 14 Liu Y, Zhang JW, Li W, Ma H, Sun J, Deng MC, Yang L. Ginsenoside metabolites, rather than naturally occurring ginsenosides, lead to inhibition of human cytochrome P450 enzymes. Toxicol Sci 2006; 91: 356-364
    CrossrefPubMedSearch in Google Scholar
  • 15 Kim SW, Kwon H, Chi DW, Shim JH, Park JD, Lee YH, Pyo S, Rhee DK. Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg(3). Biochem Pharmacol 2003; 65: 75-82
    CrossrefPubMedSearch in Google Scholar
  • 16 Zhang JW, Zhou F, Wu XL, Gu Y, Ai H, Zheng YT, Li YN, Zhang XX, Hao G, Sun JG, Peng Y, Wang GJ. 20(S)-ginsenoside Rh2 noncompetitively inhibits P-Glycoprotein in vitro and in vivo: a case for herb-drug interactions. Drug Metab Dispos 2010; 38: 2179-2187
    CrossrefPubMedSearch in Google Scholar
  • 17 Shi J, Cao B, Zha WB, Wu XL, Liu LS, Xiao WJ, Gu RR, Sun RB, Yu XY, Zheng T, Li MJ, Wang XW, Zhou J, Mao Y, Ge C, Ma T, Xia WJ, Aa JY, Wang GJ, Liu CX. Pharmacokinetic interactions between 20(S)-ginsenoside Rh2 and the HIV protease inhibitor ritonavir in vitro and in vivo . Acta Pharmacol Sin 2013; 34: 1349-1358
    CrossrefPubMedSearch in Google Scholar
  • 18 Zhang J, Zhou F, Niu F, Lu M, Wu X, Sun J, Wang G. Stereoselective regulations of P-glycoprotein by ginsenoside Rh2 epimers and the ootential mechanisms from the view of pharmacokinetics. Plos One 2012;
    PubMedSearch in Google Scholar
  • 19 Yang Z, Gao S, Wang J, Yin T, Teng Y, Wu B, You M, Jiang Z, Hu M. Enhancement of oral bioavailability of 20(S)-ginsenoside Rh2 through improved understanding of its absorption and efflux mechanisms. Drug Metab Dispos 2011; 39: 1866-1872
    CrossrefPubMedSearch in Google Scholar
  • 20 Gu Y, Wang GJ, Sun JG, Jia YW, Wang W, Xu MJ, Lv T, Zheng YT, Sai Y. Pharmacokinetic characterization of ginsenoside Rh2, an anticancer nutrient from ginseng, in rats and dogs. Food Chem Toxicol 2009; 47: 2257-2268
    PubMedSearch in Google Scholar
  • 21 Gu Y, Wang GJ, Wu XL, Zheng YT, Zhang JW, Ai H, Sun JG, Jia YW. Intestinal absorption mechanisms of ginsenoside Rh2: stereoselectivity and involvement of ABC transporters. Xenobiotica 2010; 40: 602-612
    CrossrefPubMedSearch in Google Scholar
  • 22 Kitagawa S, Takahashi T, Nabekura T, Tachikawa E, Hasegawa H. Inhibitory effects of ginsenosides and their hydrolyzed metabolites on daunorubicin transport in KB-C2 cells. Biol Pharm Bull 2007; 30: 1979-1981
    CrossrefPubMedSearch in Google Scholar
  • 23 Zhao Y, Bu L, Yan H, Jia W. 20S-protopanaxadiol inhibits P-glycoprotein in multidrug resistant cancer cells. Planta Med 2009; 75: 1124-1128
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Yang Z, Wang JR, Niu T, Gao S, Yin TJ, You M, Jiang ZH, Hu M. 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: 1538-1544
    CrossrefPubMedSearch in Google Scholar
  • 25 Liu Y, Li W, Li P, Deng MC, Yang SL, Yang L. The inhibitory effect of intestinal bacterial metabolite of ginsenosides on CYP3A activity. Biol Pharm Bull 2004; 27: 1555-1560
    CrossrefPubMedSearch in Google Scholar
  • 26 Iwanaga K, Hayashi M, Hamahata Y, Miyazaki M, Shibano M, Taniguchi M, Baba K, Kakemi M. Furanocoumarin derivatives in Kampo extract medicines inhibit cytochrome P450 3A4 and P-glycoprotein. Drug Metab Dispos 2010; 38: 1286-1294
    CrossrefPubMedSearch in Google Scholar
  • 27 Li N, Wang DD, Sui ZG, Qi XY, Ji LY, Wang XL, Yang L. Development of an improved three-dimensional in vitro intestinal mucosa model for drug absorption evaluation. Tissue Eng Part C Methods 2013;
    PubMedSearch in Google Scholar
  • 28 Zhu HJ, Wang JS, Markowitz JS, Donovan JL, Gibson BB, DeVane CL. Risperidone and paliperidone inhibit P-glycoprotein activity in vitro . Neuropsychopharmacol 2007; 32: 757-764
    CrossrefPubMedSearch in Google Scholar
  • 29 Yang LQ, Wang B, Gan H, Fu ST, Zhu XX, Wu ZN, Zhan DW, Gu RL, Dou GF, Meng ZY. Enhanced oral bioavailability and anti-tumour effect of paclitaxel by 20(s)-ginsenoside Rg3 in vivo . Biopharm Drug Dispos 2012; 33: 425-436
    CrossrefPubMedSearch in Google Scholar
  • 30 Zhang JW, Zhou F, Wu XL, Zhang XX, Chen YC, Zha BS, Niu F, Lu M, Hao G, Sun Y, Sun JG, Peng Y, Wang GJ. Cellular pharmacokinetic mechanisms of adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2 in MCF-7/Adr cells. Br J Pharmacol 2012; 165: 120-134
    CrossrefPubMedSearch in Google Scholar
  • 31 Choi CH, Kang G, Min YD. Reversal of P-glycoprotein-mediated multidrug resistance by protopanaxatriol ginsenosides from Korean red ginseng. Planta Med 2003; 69: 235-240
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Jin J, Shahi S, Kang HK, van Veen HW, Fan TP. Metabolites of ginsenosides as novel BCRP inhibitors. Biochem Biophys Res Commun 2006; 345: 1308-1314
    CrossrefPubMedSearch in Google Scholar
  • 33 Sun H, Chow ECY, Liu S, Du Y, Pang KS. The Caco-2 cell monolayer: usefulness and limitations. Expert Opin Drug Metab Toxicol 2008; 4: 395-411
    CrossrefPubMedSearch in Google Scholar
  • 34 Zhang Z, Du GJ, Wang CZ, Wen XD, Calway T, Li Z, He TC, Du W, Bissonnette M, Musch MW, Chang EB, Yuan CS. Compound K, a ginsenoside metabolite, inhibits colon cancer growth via multiple pathways including p 53-p 21 interactions. Int J Mol Sci 2013; 14: 2980-2995
    CrossrefPubMedSearch in Google Scholar
  • 35 Kim DY, Park MW, Yuan HD, Lee HJ, Kim SH, Chung SH. Compound K induces apoptosis via CAMK-IV/AMPK pathways in HT-29 colon cancer cells. J Agric Food Chem 2009; 57: 10573-10578
    CrossrefPubMedSearch in Google Scholar
  • 36 Wang H, Jiang D, Liu J, Ye S, Xiao S, Wang W, Sun Z, Xie Y, Wang J. Compound K induces apoptosis of bladder cancer T24 cells via reactive oxygen species-mediated p 38 MAPK pathway. Cancer Biother Radiopharm 2013; 28: 607-614
    CrossrefPubMedSearch in Google Scholar
  • 37 Park S, Lee HJ, Jeong SJ, Song HS, Kim M, Lee HJ, Lee EO, Kim DH, Ahn KS, Kim SH. Inhibition of JAK1/STAT3 signaling mediates compound K-induced apoptosis in human multiple myeloma U266 cells. Food Chem Toxicol 2011; 49: 1367-1372
    PubMedSearch in Google Scholar
  • 38 Liu HF, Yang JL, Du FF, Gao XM, Ma XT, Huang YH, Xu F, Niu W, Wang FQ, Mao Y, Sun Y, Lu T, Liu CX, Zhang BL, Li C. Absorption and disposition of ginsenosides after oral administration of panax notoginseng extract to rats. Drug Metab Dispos 2009; 37: 2290-2298
    CrossrefPubMedSearch in Google Scholar
  • 39 Li M, Si LQ, Pan HP, Rabba AK, Yan F, Qiu J, Li G. Excipients enhance intestinal absorption of ganciclovir by P-gp inhibition: assessed in vitro by everted gut sac and in situ by improved intestinal perfusion. Int J Pharm 2011; 403: 37-45
    CrossrefPubMedSearch in Google Scholar
  • 40 Ma B, Chai S, Li N, To KKW, Kan WLT, Yang D, Lin G. Reversal of P-glycoprotein-mediated multidrug resistance by a synthetic alpha-aminoxy peptidomimetic. Int J Pharm 2012; 424: 33-39
    CrossrefPubMedSearch in Google Scholar