Ginsenoside as a Prodrug:

Effect of its Active Metabolites on Cancer MetastasisCancer Metastasis

Wonkwang University

Dept of PharmacyDept of Pharmacy

Dong-Hwan Sohn

Suh SO et al. (2002) Effects of red ginseng uponSuh SO et al. (2002) Effects of red ginseng upon postoperative immunity and survival in patients with stage III gastric cancer. Am J Chin Med. 30(4):483-94.

“ …. This study demonstrated a five-year disease free survival and overall survival rate that was significantly higher in patients taking the red ginseng powder duringhigher in patients taking the red ginseng powder during postoperative chemotherapy versus control (68.2% versus 33.3%, 76.4% versus 38.5%, respectively, p < 0.05). In spite of the limitation of a small number of patients (n = 42)spite of the limitation of a small number of patients (n 42), these findings suggest that red ginseng powder may help to improve postoperative survival in these patients. ….”

Main Biologically Active Constituents: Main iologically Active Constituents

Saponins ( ~ 31 ea)

Poor absorption of ginsenoside from the intestine : less than 3%intestine : less than 3%

The transformation of ginsenosides by human The transformation of ginsenosides by human intestinal bacteria after oral administration.

Good absorption of active metabolites

21% of human fecal specimens shows no hydrolyzing potentialhydrolyzing potential.

Major intestinal bacteria: Prevotella Oris Major intestinal bacteria: Prevotella Oris

Inhibitory effect by oral adminstration of M1 on tumor metastasistumor metastasis

A i ti f A ti t t ti ff t f Rb1 ith Association of Antimetastastic effect of Rb1 with bacterial Rb1-hydrolyzing potentials

In vitro effect on metastasizing cell function

ginsenosides Metaboliteginsenosides Metabolite

Tumor cell proliferation

inhibition - +

Tumor cell invasion inhibition

- +

Tumor cell adhesion+

inhibition- +

Ph ki ti fi f M1 Pharmacokinetic profie of M1

Fig 1. Mean plasma concentration-time profiles of compound K in rats after intravenous injection of the drug at 1 (), 2 () and 10 () mg/kg (n = 7). Vertical bars represent standard deviation

Table 1. Pharmacokinetic parameters of compound K after iv injection of various doses to rats (n = 7)aTable 1. Pharmacokinetic parameters of compound K after iv injection of various doses to rats (n 7)

Parameters 1 mg/kg 2 mg/kg 10 mg/kg

Body weight (g) 270 ± 9.9 284 ± 16.0 262 ± 11.1

t1/2 (min) 222 ± 82.5 298 ± 77.9 224 ± 115

AUC (gmin/ml)b 41.8 ± 28.9 115.6 ± 6.8 486.8 ± 188.2

MRT (min) 81.1 ± 31.8 96.1 ± 54.8 79.9 ± 40.5

CL (ml/min/kg) 31.3 ± 14.8 17.3 ± 1.0 23.1 ± 8.4

Vss (ml/kg) 2744 ± 2050 1677 ± 1001 1757 ± 750( g) 1677 1001

Ae0-24h (% of dose) 0.008 ± 0.008 0.009 ± 0.002 0.006 ± 0.002

GI24h (% of dose) 26.2 ± 3.2 25.2 ± 10.3 24.4 ± 10.4

aValues expressed as mean ± SD.bDose-normalized (1 mg/kg) AUCs were compared by statistical analysis.

Fig 2. Mean plasma concentration-time profiles of compound K in rats after oral administration of the drug at 5 (, n = 7), 10 (, n = 8) and 20 (, n = 10) mg/kg. Vertical bars represent standard deviation

T bl 2 Ph ki i f d K f l d i i i f i dTable 2. Pharmacokinetic parameters of compound K after oral administration of various doses to ratsa

Parameters 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 ± 11.5

AUC (gmin/ml)b 4.50 ± 3.86 21.0 ± 28.8 341.0 ± 201.8c

Tmax (min) 124 ± 162 191 ± 196 151 ± 122max ( )

Cmax (g/ml)b 0.028 ± 0.023 0.078 ± 0.098 0.726 ± 0.386c

Ae0-24h (% of dose) BDd BDd BDd

GI (% of dose) 54 3 ± 21 5 81 7 ± 26 8 77 5 ± 15 3GI24h (% of dose) 54.3 ± 21.5 81.7 ± 26.8 77.5 ± 15.3

F (%) 1.8 4.3 35.0

aValues expressed as mean ± SD.bDose normali ed (5 mg/kg) AUCs were compared by statistical analysisbDose-normalized (5 mg/kg) AUCs were compared by statistical analysis.c20 mg/kg was significantly different (p<0.05) from 5 and 10 mg/kg.

M t b li f M1 Metabolism of M1

Enhancement of antitumor effect of M1 by fatty-acid esterificationesterification

SummarySummary

The transformation of ginsenosides by human intestinal The transformation of ginsenosides by human intestinal bacteria after oral administration.

Good absorption of active metabolites Good absorption of active metabolites

21% of human fecal specimens shows no hydrolyzing potentialpotential.

Inhibitory effect by oral adminstration of M1 on tumor metastasismetastasis

Association of Antimetastastic effect of Rb1 with bacterial Rb1-hydrolyzing potentialsRb1 hydrolyzing potentials

Acknowledgements

The late Dr Hideo Hasegawa (Fermenta Herb Institute Japan)

Acknowledgements

The late Dr. Hideo Hasegawa (Fermenta Herb Institute, Japan)

The late Prof. Emeritus Kim, Jaebaek (Wonpharm. Co. Ltd., Korea)

Dr Lee Hye-Sook (Catholic Univ Korea) Dr. Lee, Hye-Sook (Catholic Univ., Korea)