2.ginsenoside metabolite 경희대(손동환)

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2.ginsenoside metabolite 경희대(손동환)

  1. 1. Ginsenoside as a Prodrug:Effect of its Active Metabolites on Cancer Metastasis Wonkwang University Dept of Pharmacy Dong-Hwan Sohn
  2. 2. Suh SO et al. (2002) Effects of red ginseng uponpostoperative immunity and survival in patients with stage IIIgastric cancer. Am J Chin Med. 30(4):483-94.“ …. This study demonstrated a five-year disease freesurvival and overall survival rate that was significantlyhigher in patients taking the red ginseng powder duringpostoperative chemotherapy versus control (68.2% versus33.3%, 76.4% versus 38.5%, respectively, p < 0.05). Inspite of the limitation of a small number of patients (n = 42) 42),these findings suggest that red ginseng powder may helpto improve postoperative survival in these patients. ….”
  3. 3.  Main Biologically Active Constituents iologically Constituents: Saponins ( ~ 31 ea)
  4. 4.  Poor absorption of ginsenoside from the intestine : less than 3% The transformation of ginsenosides by human intestinal bacteria after oral administration. Good absorption of active metabolites
  5. 5.  21% of human fecal specimens shows no hydrolyzing potential potential. Major intestinal bacteria: Prevotella Oris
  6. 6.  Inhibitory effect by oral adminstration of M1 on tumor metastasis
  7. 7. A Association of A ti t t ti effect of Rb1 with i ti f Antimetastastic ff t f ith bacterial Rb1-hydrolyzing potentials
  8. 8. In vitro effect on metastasizing cell function ginsenosides Metabolite Tumor cell proliferation - + inhibition Tumor cell invasion - + inhibition Tumor cell adhesion - + inhibition
  9. 9.  Ph Pharmacokinetic profie of M1 ki ti fi f
  10. 10. Fig 1. Mean plasma concentration-time profiles of compound K in rats after intravenousinjection of the drug at 1 (), 2 () and 10 () mg/kg (n = 7). Vertical bars representstandard deviation
  11. 11. Table 1. Pharmacokinetic parameters of compound K after iv injection of various doses to rats (n = 7)aParameters 1 mg/kg 2 mg/kg 10 mg/kgBody weight (g) 270 ± 9.9 284 ± 16.0 262 ± 11.1t1/2 (min) 222 ± 82.5 298 ± 77.9 224 ± 115AUC (gmin/ml)b 41.8 ± 28.9 115.6 ± 6.8 486.8 ± 188.2MRT (min) 81.1 ± 31.8 96.1 ± 54.8 79.9 ± 40.5CL (ml/min/kg) 31.3 ± 14.8 17.3 ± 1.0 23.1 ± 8.4Vss (ml/kg) ( g) 2744 ± 2050 1677 ± 1001 1757 ± 750Ae0-24h (% of dose) 0.008 ± 0.008 0.009 ± 0.002 0.006 ± 0.002GI24h (% of dose) 26.2 ± 3.2 25.2 ± 10.3 24.4 ± 10.4aValues expressed as mean ± SD.bDose-normalized (1 mg/kg) AUCs were compared by statistical analysis.
  12. 12. Fig 2. Mean plasma concentration-time profiles of compound K in rats after oraladministration of the drug at 5 (, n = 7), 10 (, n = 8) and 20 (, n = 10) mg/kg.Vertical bars represent standard deviation
  13. 13. T bl 2. Pharmacokinetic parameters of compound K after oral administration of various doses to ratsaTable 2 Ph ki i f d f l d i i i f i dParameters 5 mg/kg (n=7) 10 mg/kg (n=8) 20 mg/kg (n=10)Body weight (g) 245 ± 14.6 254 ± 18.4 224 ± 11.5AUC (gmin/ml)b 4.50 ± 3.86 21.0 ± 28.8 341.0 ± 201.8cTmax (min) ( ) 124 ± 162 191 ± 196 151 ± 122Cmax (g/ml)b 0.028 ± 0.023 0.078 ± 0.098 0.726 ± 0.386cAe0-24h (% of dose) BDd BDd BDdGI24h (% of dose) 54.3 21.5 54 3 ± 21 5 81.7 26.8 81 7 ± 26 8 77.5 15.3 77 5 ± 15 3F (%) 1.8 4.3 35.0 aValuesexpressed as mean ± SD. bDose normali ed Dose-normalized (5 mg/kg) AUCs were compared by statistical analysis analysis. c20 mg/kg was significantly different (p<0.05) from 5 and 10 mg/kg.
  14. 14.  M t b li Metabolism of M1 f Enhancement of antitumor effect of M1 by fatty-acid esterification
  15. 15. Summary The transformation of ginsenosides by human intestinal bacteria after oral administration. Good absorption of active metabolites 21% of human fecal specimens shows no hydrolyzing potential. potential Inhibitory effect by oral adminstration of M1 on tumor metastasis Association of Antimetastastic effect of Rb1 with bacterial Rb1 hydrolyzing Rb1-hydrolyzing potentials
  16. 16. Acknowledgements The late Dr. Hideo Hasegawa (Fermenta Herb Institute Japan) Dr Institute, The late Prof. Emeritus Kim, Jaebaek (Wonpharm. Co. Ltd., Korea) Dr Lee Hye-Sook (Catholic Univ Korea) Dr. Lee, Univ.,

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