Abstract
We aimed to investigate the effects of red ginseng extract (RGE) on the expression of efflux transporters and to study the pharmacokinetics of representative substrate. For this, rats received single or repeated administration of RGE (1.5 g/kg/day) for 1 and 2 weeks via oral gavage. mRNA and protein levels of multidrug resistance-associated protein2 (Mrp2), bile salt export pump (Bsep), and P-glycoprotein (P-gp) in the rat liver were measured via real-time polymerase chain reaction and Western blot analysis. Ginsenosides concentrations from the rat plasma were also monitored using a liquid chromatography–tandem mass spectrometry (LC–MS/MS) system. Plasma concentrations of ginsenoside Rb1, Rb2, Rc, and Rd following repeated administration of RGE for 1 and 2 weeks were comparable but significantly higher than those after single administration of RGE. These dosing regimens did not induce significant biochemical abnormalities in the liver, kidneys, and lipid homeostasis. In the RGE repeated oral administration groups, the mRNA and protein levels of Mrp2 significantly decreased. Accordingly, we investigated the changes in the pharmacokinetics of methotrexate, a probe substrate for Mrp2, following intravenous administration of 3 mg/kg methotrexate to rats in the RGE 1-week repeated oral administration group, compared to that in the control group. Biliary excretion, but not urinary excretion, of methotrexate decreased in the RGE repeated administration group, compared to that in the control group. Consequently, the plasma concentrations of methotrexate slightly increased in the RGE repeated administration group. In conclusion, repeated administration of RGE for 1 week resulted in a decrease in Mrp2 expression without inducing significant liver or kidney damage. Pharmacokinetic herb–drug interaction between RGE and methotrexate might occur owing to the decrease in the mRNA and protein levels of Mrp2.
Highlights
Peaks of the other six ginsenosides (Rh2, F2, compound K, protopanaxadiol, F1, and protopanaxatriol) were not detected since these ginsenosides are minor components and are biological metabolites of Rb1, Rb2, Re, or Rg1 that could be produced via metabolism in the gut microflora [24,25]
The contents of ginsenosides could differ depending on the preparation procedure for red ginseng extract (RGE); the contents of major ginsenosides, such as Rb1, Rb2, Rc, and Rg3, were comparable to previously reported values [26,27]
RGE treatment at a daily dose of 1.5 g/kg for 1 week resulted in steady-state plasma concentrations of major ginsenosides, such as Rb1, Rb2, Rc, and Rd (Table 2)
Summary
Ginseng (the roots and rhizomes of Panax ginseng C.A. Meyer) has been extensively used for more than 2000 years in East Asian countries [1,2]. Red ginseng extract (RGE) is produced from. 6-year-old fresh ginseng by steaming and drying, which leads to biochemical transformation of various ginsenosides [3]. Ginsenosides are considered the major active pharmacological constituents of ginseng. They have been shown to exhibit anti-neoplastic, anti-hypertensive, anti-diabetic, anti-inflammatory, anti-oxidant, anti-allergic, neuroprotective, and immunological effects [4,5,6,7].
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