Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation

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.

Herb–Drug Interaction of Red Ginseng Extract and Ginsenoside Rc with Valsartan in Rats

“…Among the 14 ginsenosides examined (Rb1, Rb2, Rc, Rd, Rh2, Rg3, F2, compound K, PPD, Re, Rh1, Rg1, F1, and PPT), 6 ginsenosides were detected in the plasma samples and the plasma concentrations of the 6 ginsenosides are shown in Figure 6. The plasma concentrations of the ginsenosides Rb1, Rb2, Rc, and Rd in rats after multiple administration of RGE (1.5 g/kg/day) for 1 week were consistent with previous results [8,19]. The ginsenosides Rh2, Rg3, F2, and compound K (intermediate metabolites of PPD-type ginsenosides [32], were not detected.…”

“…In another study using rats, the bioavailability of fexofenadine was decreased by 16.1% following repeated administration of ginseng radix extract (150 mg/kg/day for 2 weeks), which may be explained by reduced absorption of fexofenadine due to the induction of intestinal P-gp [18]. Repeated RGE treatment was reported to decrease multidrug resistance-related protein 2 (Mrp2) mRNA and protein expression, consequently decreasing the biliary excretion of methotrexate and increasing plasma concentration [8]. Intestinal and hepatic organic cation transporter 1 (Oct1) expression was increased and decreased, respectively, in rats following repeated administration of RGE (1.5 g/kg for 7 days) [19].…”

“…Ginseng is one of the most popular plants in Asia, Europe, and USA [1,2] owing to its vitality restoration and immunostimulating effect [1]. The therapeutic benefits of ginseng include anti-diabetic and anti-inflammatory effect and anti-oxidative response on chronic liver disease [3][4][5][6][7][8]. Ginseng is also commonly used due to its potential as a chemo-preventive agent and adjuvant therapy [9].…”

“…The most frequently reported cases of herb-drug interactions include the modulation of drug metabolizing enzymes and transporters by herbal medicines and the causative pharmacokinetic alterations of co-administered therapeutic drugs that may acts as substrates for drug metabolizing enzymes and transporters [8,11]. In case of ginseng interactions, it was reported that no herb-drug interaction between single oral dose of Korean red ginseng extract (RGE) (0.5-2.0 g/kg) and the probe substrates for five cytochrome P450 (CYP) enzymes (i.e., CYP1A2, 2C9, 2C19, 2D6, 3A) in mouse [12].…”

The Development and Validation of a Novel “Dual Cocktail” Probe for Cytochrome P450s and Transporter Functions to Evaluate Pharmacokinetic Drug-Drug and Herb-Drug Interactions

“…Although this cocktail set included probes that are substrates for the OATPs and P-gp transporters, the use of transporter-targeted cocktails is still limited [ 11 ]. However, drug transporters are significant determinant of the pharmacokinetic features of drugs, and several clinically relevant DDIs or HDIs were mediated through drug transporter inhibition, as evidenced by numerous reports in the literature [ 1 , 12 , 13 ]. Therefore, this study aimed to develop a combination of dual cocktails that consists of five drugs as probes for CYP metabolizing enzyme function and five drugs as probes for transporter function to simultaneously monitor potential pharmacokinetic DDIs or HDIs in rats in vivo.…”