Concomitant Administration of Red Ginseng Extract with Lactic Acid Bacteria Increases the Plasma Concentration of Deglycosylated Ginsenosides in Healthy Human Subjects

Abstract

With the increased frequency of red ginseng extract (RGE) and lactic acid bacteria (LAB) co-administration, we aimed to investigate the interactions between RGE and LAB with regard to in vitro and in vivo deglycosylation metabolism and the pharmacokinetics of ginsenosides. As a proof-of-concept study, five healthy humans were administered RGE (104.1 mg of total ginsenosides/day) with or without co-administration of LAB (2 g, 1 billion CFU/day) for 2 weeks, and the plasma concentrations of ginsenosides in human plasma were monitored. The plasma exposure to compound K (CK), ginsenoside Rh2 (GRh2), protopanaxadiol (PPD), and protopanaxatriol (PPT) in the concomitant administration RGE and LAB groups increased by 2.7-, 2.1-, 1.6-, and 3.5-fold, respectively, compared to those in the RGE administration group, without a significant change in T_max. The plasma concentrations of GRb1, GRb2, and GRc remained unchanged, whereas the AUC values of GRd and GRg3 significantly decreased in the concomitant administration RGE and LAB groups. To understand the underlying mechanism, the in vitro metabolic activity of ginsenosides was measured during the fermentation of RGE or individual ginsenosides in the presence of LAB for 1 week. Consistent with the in vivo results, co-incubation with RGE and LAB significantly increased the formation rate of GRh2, CK, PPD, and PPT. These results may be attributed to the facilitated deglycosylation of GRd and GRg3 and the increased production of GRh2, CK, PPD, and PPT by the co-administration of LAB and RGE. In conclusion, LAB supplementation increased the plasma concentrations of deglycosylated ginsenosides, such as GRh2, CK, PPD, and PPT, through facilitated deglycosylation metabolism of ginsenosides in the intestine.

Keywords: deglycosylation metabolism; ginsenosides; lactic acid bacteria (LAB); pharmacokinetics; red ginseng extract (RGE).

Figure 1

(A) Chemical structures of the PPD-type and PPT-type ginsenosides. Glc: glucose; Arap: arabinopyranose; Araf: arabinofuranose; Rha: rhamnose; Xyl: xylose. (B) Alterations of 15 ginsenosides following the incubation of RGE with LAB for 7 days are expressed as the relative percentage of ginsenoside. Metabolic activity of (C) the PPD-type ginsenosides and (D) the PPT-type ginsenosides following incubation of RGE (100 μg) with LAB (1 billion CFU), expressed as the alteration of the ginsenoside amount per day depending on the sugar number (No.) of the ginsenosides. Data points are represented as mean ± standard deviation (n = 4). * p < 0.05 compared with after LAB incubation group.

Figure 2

Plasma concentration-time profile of ginsenoside Rb1 (GRb1), GRb2, GRc, GRd, GRg3, GRh2, CK, PPD, and PPT in humans following the repeated oral administration of RGE for 14 days with or without repeated co-administration of LAB for 14 days (●: RGE; ○: RGE + LAB). The data points are represented as mean ± standard deviation (n = 5).

Figure 3

(A) Correlation between ginsenoside content and AUC values of ginsenosides after oral administration of RGE. The data are taken from Table 1 and Figure 1A. Lines were generated from the linear regression analysis and 90% confidence intervals. (B) T_max of ginsenosides was drawn depending on the sugar No. of the ginsenosides (● and ▼: RGE; ○ and ∆: RGE + LAB). (C) AUC of ginsenosides was drawn depending on the sugar No. of the ginsenosides; * p < 0.05 was considered statistically significant between the two groups; the data are taken from Table 1. Data points are represented as mean ± standard deviation (n = 5).

Figure 4

Metabolic activity of deglycosylated ginsenosides following incubation of each ginsenoside (10 μM each) with LAB (1 billion CFU) for 7 days. (A) PPD-type ginsenosides: GRb1, GRb2, GRc, GRd, GF2, GRg3, CK, and GRh2 and (B) PPT-type ginsenosides: GRf, GRe, GRg1, GF1, and GRh1 were incubated in the presence of LAB for 7 days. The data are expressed as mean ± standard deviation (n = 4). (C) PPD- and PPT-type ginsenosides were grouped by sugar number and deglycosylation pathway. Arrows indicate the relative deglycosylation activity at the −C3, −C6, or −C20 positions of ginsenosides by incubating with LAB from the results in (A,B). Glc; glucose residue.

Figure 5

(A) The permeability (P_app) of PPD-type ginsenosides and PPT-type ginsenosides from apical to basal (A to B) and B to A direction was measured in CaCo-2 cell monolayers. The efflux ratio (ER) was calculated by dividing B to A P_app by A to B P_app. (B) A to B and B to A permeability of GRg3, CK, GRh2, PPD, GRg1, GRh1, and PPT in LLC-PK1-P-gp cells. (C) Kinetic parameters of CK, GRh2, PPD, and PPT in LLC-PK1-P-gp cells. (D) Concentration dependency for the B to A transport rate of CK, GRh2, PPD, and PPT was measured in LLC-PK1-P-gp cells. A line was generated from the Michaelis–Menten equation. Data are expressed as mean± standard deviation (n = 3).