Enhanced Intestinal Permeability and Plasma Concentration of Metformin in Rats by the Repeated Administration of Red Ginseng Extract

Abstract

We aimed to assess the potential herb-drug interactions between Korean red ginseng extract (RGE) and metformin in rats in terms of the modulation of metformin transporters, such as organic cation transporter (Oct), multiple toxin and extrusion protein (Mate), and plasma membrane monoamine transporter (Pmat). Single treatment of RGE did not inhibit the in vitro transport activity of OCT1/2 up to 500 µg/mL and inhibited MATE1/2-K with high IC₅₀ value (more than 147.8 µg/mL), suggesting that concomitant used of RGE did not directly inhibit OCT- and MATE-mediated metformin uptake. However, 1-week repeated administration of RGE (1.5 g/kg/day) (1WRA) to rats showed different alterations in mRNA levels of Oct1 depending on the tissue type. RGE increased intestinal Oct1 but decreased hepatic Oct1. However, neither renal Oct1/Oct2 nor Mate1/Pmat expression in duodenum, jejunum, ileum, liver, and kidney were changed in 1WRA rats. RGE repeated dose also increased the intestinal permeability of metformin; however, the permeability of 3-O-methyl-d-glucose and Lucifer yellow was not changed in 1WRA rats, suggesting that the increased permeability of metformin by multiple doses of RGE is substrate-specific. On pharmacokinetic analysis, plasma metformin concentrations following intravenous injection were not changed in 1WRA, consistent with no significant change in renal Oct1, Oct2, and mate1. Repeated doses of RGE for 1 week significantly increased the plasma concentration of metformin, with increased half-life and urinary excretion of metformin following oral administration of metformin (50 mg/kg), which could be attributed to the increased absorption of metformin. In conclusion, repeated administration of RGE showed in vivo pharmacokinetic herb-drug interaction with metformin, with regard to its plasma exposure and increased absorption in rats. These results were consistent with increased intestinal Oct1 and its functional consequence, therefore, the combined therapeutic efficacy needs further evaluation before the combination and repeated administration of RGE and metformin, an Oct1 substrate drug.

Keywords: herb–drug interaction; intestinal permeability; metformin; organic cation transporter; red ginseng extract (RGE).

Figure 1

Inhibitory effect of cimetidine (A–D) and Korean red ginseng extract (RGE) (E–H) on organic cation transporter 1 (OCT1), OCT2, multiple toxin and extrusion protein 1 (MATE1), and MATE2-K-mediated uptake of metformin. Effect of cimetidine (0.01 µM–10 mM) and RGE (0.1–500 µg/mL) on uptake of 10 µM [¹⁴C]metformin in HEK293 cells overexpressing OCT1, OCT2, MATE1, and MATE2-K transporters was measured for 5 min. Data points represent means ± SD of three independent experiments. Data were fitted to an inhibitory effect Sigmoid Emax model and the IC₅₀ value was calculated.

Figure 2

The mRNA expression of organic cation transporter 1 (Oct1) (A), Oct2 (B), multiple toxin and extrusion protein 1 (Mate1) (C), and plasma membrane monoamine transporter (Pmat) (D) in the duodenum, jejunum, ileum, liver, and kidney of rats in control, single RGE treatment (SA), and 1-week repeated RGE administration (1WRA) groups. Bars represent mean ± SD of three independent analyses; * p < 0.05 compared with control group (by Student’s t-test).

Figure 3

Protein expression of organic cation transporter 1 (Oct1) in the ileal enterocytes, liver, and kidney and Oct2 in the kidney of rats in control (lanes a, b, and c), single RGE treatment (SA, lanes d, e, and f), and 1-week repeated RGE administration (1WRA, lanes g, h, and i) groups and β-actin was used as a loading control. Quantitative analysis of western blot results is shown in the lower panel. Bars are mean ± SD of three independent densitometric analyses; * p < 0.05 compared with control group (by Student’s t-test).

Figure 4

Intestinal absorptive permeability (P_app) of metformin (A), 3-O-methyl-d-glucose (B), and Lucifer yellow (C) was measured in duodenum, jejunum, and ileum segments from rats of control, single RGE treatment (SA), and 1-week repeated RGE administration (1WRA) groups. Data points represent the mean ± SD from three different rats per group; * p < 0.05 compared with control group (by Student’s t-test).

Figure 5

Plasma concentration-time profile of metformin in control, single administration of RGE (SA), and 1-week repeated RGE administration (1WRA, 1.5 g/kg/day) group following intravenous injection (IV) of metformin at a dose of 0.25 mg/kg (A) and oral administration (PO) of metformin at a dose of 50 mg/kg (B) Data points represent the mean ± SD from five different rats per group.