Global deregulation of ginseng products may be a safety hazard to warfarin takers: solid evidence of ginseng-warfarin interaction

Abstract

Recent global deregulation of ginseng as the table food raises our concern about the possible ginseng-warfarin interaction that could be life-threatening to patients who take warfarin for preventing fatal strokes and thromboembolism while using ginseng products for bioenergy recovery. Here we show that quality-control ginsenosides, extracted from ginseng and containing its major active ingredients, produce dose- and time-dependent antagonism in rats against warfarin’s anti-coagulation assessed by INR and rat thrombosis model. The interactions between ginsenosides and warfarin on thrombosis, pharmacokinetics, activities of coagulation factors and liver cytochrome P450 isomers are determined by using thrombosis analyzer, UPLC/MS/MS, ELISA and real-time PCR, respectively. The antagonism correlates well with the related pharmacokinetic interaction showing that the blood plateaus of warfarin reached by one-week warfarin administration are significantly reduced after three-week co-administration of warfarin with ginsenosides while 7-hydroxywarfarin is increased. The one-week warfarin and three-week warfarin-ginsenosides regimen result in restoring the suppressed levels by warfarin of the coagulating factors II, VII and protein Z, and significantly enhance activities of P450 3A4 and 2C9 that metabolize warfarin. The present study, for the first time, provides the solid evidence to demonstrate the warfarin-ginsenoside interaction, and warns the warfarin users and regulation authorities of the dangerous interaction.

Herbal Medicine for Cardiovascular Diseases: Efficacy, Mechanisms, and Safety

“…A randomized, double-blind, placebo-controlled trial using 20 healthy patients concluded that a 2-week intake of American Ginseng (2 g/d; 1 g twice daily) significantly reduced peak international normalized ratio (INR) and peak plasma warfarin levels (Yuan et al, 2004). In a recent study performed on rats, ginsenosides were reported to significantly enhance the activity of two enzymes known to metabolize warfarin, P450 CYP3A4 and P450 CYP2C9, restoring the levels of coagulation factors II and VII and that of the protein Z, that are usually suppressed by warfarin (Dong et al, 2017). The combined use of Panax ginseng with the monoamine oxidase inhibitor, phenelzine (Nardil), may result in manic-like symptoms (Vogler et al, 1999).…”

Hemorrhage After Lunch?

“…It has been suggested that this is due to induction of CYP 3A4 and CYP2C9 enzymes by ginsenosides [21]. St Jone's wort can produce similar effect.…”

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

“…To validate the dual cocktail set, a single oral dose of ketoconazole (10 mg/kg) as a representative Cyp3a inhibitor [ 51 ], a single oral dose of rifampin (20 mg/kg) as a representative Oatp inhibitor [ 21 ], and multiple oral doses of rifampin (20 mg/kg/dy for five days) as a representative Cyp3a and P-gp inducer [ 52 , 53 ] were administered before the dual cocktail substrates. Rifampin and ketoconazole has been widely used to investigate the pharmacokinetic DDIs in human as well as in animals [ 54 , 55 ].…”

“…In summary, the dual cocktail of 10 probe substrates for five CYPs and five transporters was successfully developed without any significant pharmacokinetic DDIs among the probe substrates. This dual cocktail was validated using a representative Cyp3a inhibitor ketoconazole, an Oatp inhibitor rifampin (single administration) [ 21 ], and a repeated rifampin administration, which acts as a Cyp3a and P-gp inducer [ 52 , 53 ].…”

“…P-gp (P-gp in rat), organic anion transporters (OATs; Oats in rat), organic cation transporters (OCTs; Octs in rat), multidrug resistance-associated protein 2 (MRP2; Mrp2 in rat), and OATPs (Oatps in rat) were selected as the key drug transporters involved in DDIs [ 11 ]. Digoxin (2 mg/kg), furosemide (0.1 mg/kg), metformin (0.5 mg/kg), methotrexate (0.5 mg/kg), and valsartan (0.2 mg/kg) were selected as their probe substrates because Octs, Oats, P-gp, and Mrp2 play significant roles in the disposition and plasma profile of these substrate drugs [ 11 , 13 , 20 , 21 ]. These substrates were intravenously administered due to their low bioavailability, which is below 30% [ 13 , 22 , 23 , 24 , 25 , 26 ].…”