Ginseng (Panax ginseng Meyer) is a well-known health functional food used as a traditional herbal drug in Asian countries owing to its diverse pharmacological effects. Herb-drug interactions may cause unexpected side effects of co-administered drugs by the alteration of pharmacokinetics through effects on cytochrome P450 activity. In this study, we investigated the herb-drug interactions between Korean red ginseng extract (KRG) and five CYP-specific probes in mice. The pharmacokinetics of KRG extract induced-drug interactions were studied by cassette dosing of five CYP substrates for CYP1A, 2B, 2C, 2D, and 3A and the LC-MS/MS analysis of the blood concentration of metabolites of each of the five probes. The linearity, precision, and accuracy of the quantification method of the five metabolites were successfully confirmed. The plasma concentrations of five metabolites after co-administration of different doses of the KRG extract (0, 0.5, 1, and 2 g/kg) were quantified by LC-MS/MS and dose-dependent pharmacokinetic parameters were determined. The pharmacokinetic parameters of the five metabolites were not significantly altered by the dose of the KRG extract. In conclusion, the single co-administration of KRG extract up to 2 g/kg in vivo did not cause any significant herb-drug interactions linked to the modulation of CYP activity.
Korean ginseng (Panax ginseng Meyer) is a traditional herb used across the world to treat various diseases. Although, red ginseng is this herb’s most famous product and has demonstrated diverse pharmacological activities, white ginseng (WG) is another ginseng product that is made fresh and individually regulated in Eastern Asia. Red and white ginseng show different characteristics due to distinct processing steps despite originating from the same plant, and the drug interactions induced by WG have not been well documented. Selegiline is a selective monoamine oxidase (MAO) inhibitor used as an antidyskinetic and antiparkinsonian agent. Here we developed a quantification method for selegiline in mouse plasma using a C8 stationary phase in triple quadrupole-mass spectrometry (LC-MS/MS) with multiple reaction monitoring (MRM). The validated LC-MS/MS method was successfully applied to determine the potential interaction with WG extract (0.1 g/kg/day) pre-administered for 4 weeks. The AUC 0-240 min of selegiline was altered due to a decrease in the absorption of selegiline with repeated administration of WG extract.
Previous in vitro studies have demonstrated that ginsenoside Rc inhibits UGT1A9, but there are no available data to indicate that ginsenoside Rc inhibits UGT1A9 in vivo. The effect of single and repeated intravenous injection of ginsenoside Rc was evaluated on the pharmacokinetics of mycophenolic acid. After injection of ginsenoside Rc (5 mg/kg for one day or 3 mg/kg for five days), 2-mg mycophenolic acid was intravenously injected, and the pharmacokinetics of mycophenolic acid and mycophenolic acid-β-glucuronide were determined. Concentrations of mycophenolic acid and its metabolite from rat plasma were analyzed using a liquid chromatography-triple quadrupole mass spectrometry. Single or repeated pretreatment with ginse-noside Rc had no significant effects on the pharmacokinetics of mycophenolic acid (P > 0.05): The mean difference in maximum plasma concentration (C max ) and area under the concentration-time curve (AUC inf ) were within 0.83- and 0.62-fold, respectively, compared with those in the absence of the ginsenoside Rc. These results indicate that ginsenoside Rc has a negligible effect on the disposition of mycophenolic acid in vivo despite in vitro findings indicating that ginsenoside Rc is a selective UGT1A9 inhibitor. As a result, ginsenoside Rc has little possibility of interacting with drugs that are metabolized by UGT1A9, including mycophenolic acid.
Ginseng, a traditional herbal drug, has been used in Eastern Asia for more than 2000 years. Various ginsenosides, which are the major bioactive components of ginseng products, have been shown to exert numerous beneficial effects on the human body when co-administered with drugs. However, this may give rise to ginsenoside-drug interactions, which is an important research consideration. In this study, acassette assay was performed the inhibitory effects of 12 ginsenosides on seven cytochrome P450 (CYP) isoforms in human liver microsomes (HLMs) using LC-MS/MS to predict the herb-drug interaction. After incubation of the 12 ginsenosides with seven cocktail CYP probes, the generated specific metabolites were quantified by LC-MS/MS to determine their activities. Ginsenoside Rb1 and F2 showed strong selective inhibitory effect on CYP2C9-catalyzed diclofenac 4′-hydroxylation and CYP2B6-catalyzed bupropion hydroxylation, respectively. Ginsenosides Rd showed weak inhibitory effect on the activities of CYP2B6, 2C9, 2C19, 2D6, 3A4, and compound K, while ginsenoside Rg3 showed weak inhibitory effects on CYP2B6. Other ginsenosides, Rc, Rf, Rg1, Rh1, Rf, and Re did not show significant inhibitory effects on the activities of the seven CYPs in HLM. Owing to the poor absorption of ginsenosides after oral administration in vivo, ginsenosides may not have significant side effects caused by interaction with other drugs.
Mollugin isolated from Rubia cordifolia is known to have anti-inflammatory, anti-cancer, and anti-viral activities. Inthe present study, a cocktail probe assay and LC-MS/MS were used to investigate the modulating effect of mollugin on cytochromeP450 (CYP) enzymes in male ICR mice. After mollugin was orally administrated to mice at the 20, 40, or 80 mg/kg for3 days, the activities of CYP in hepatic S-9 fractions were investigated. Unlike the selective inhibitory effect of mollugin onCYP1A2-catalyzed phenacetin O-deethylation in vitro, mollugin only significantly inhibited the activity of CYP2E1-catalyzedchlorzoxazone 6-hydroxylase in vivo. The activities of other CYPs were only slightly altered by mollugin. The results of thisstudy suggest that mollugin might cause herb-drug interactions via the selective inhibition of CYP2E1 in vivo.
Licoricidin isolated from Glycyrrhiza uralensis is known to have anticancer, anti-nephritic, anti-Helicobacter pylori,and antibacterial effects. In this study, a cocktail probe assay and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to investigate the modulating effect of licoricidin on cytochrome P450 (CYP) enzymes in human livermicrosomes. When licoricidin was incubated at 0-25 μM with CYP probes for 60 min at 37oC, it showed potent inhibitoryeffects on CYP2B6-catalyzed bupropion hydroxylation and CYP2C9-catalyzed diclofenac 4’-hydroxylation with half maximalinhibitory concentration (IC50) values of 3.4 and 4.0 μM, respectively. The inhibition mode of licoricidin was revealed as competitive,dose-dependent, and non-time-dependent, and following the pattern of Lineweaver-Burk plots. The inhibitory effect oflicoricidin has been confirmed in human recombinant cDNA-expressed CYP2B6 and 2C9 with IC50 values of 4.5 and 0.73 μM,respectively. In conclusion, this study has shown the potent inhibitory effect of licoricidin on CYP2B6 and CYP2C9 activitycould be important for predicting potential herb-drug interactions with substrates that mainly undergo CYP2B- and CYP2C9-mediated metabolism.