Abstract
BackgroundRadix Salvia miltiorrhiza (Danshen) and Radix Puerariae lobatae (Gegen) are used in Traditional Chinese Medicine to treat cardiovascular diseases. However, adverse herb-drug interactions were observed between warfarin and herbal remedies containing Danshen and Gegen. This study aims to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and the different components found in Danshen and Gegen.MethodsSixty Sprague–Dawley rats were used to investigate the effects of warfarin (0.2 mg/kg), Danshen (240 or 480 mg/kg) and Gegen (240 or 480 mg/kg) both in isolation and combination. The rats in the warfarin and Danshen/Gegen combination groups were given an oral dose of Danshen or Gegen 2 h after being given an oral dose of warfarin. After five consecutive days of treatment, the pharmacokinetic interactions between Danshen/Gegen and warfarin were investigated by simultaneously monitoring and comparing the cytochrome P450 (CYP) activities, mRNA and protein expression levels in the livers of the rats from the different treatment groups. The pharmacodynamic interactions were evaluated by monitoring and comparing the vitamin K epoxide reductase (VKOR) activities, mRNA and protein expression levels in the livers of rats from the different groups, as well as the thrombomodulin (TM) activities, mRNA and protein in the lungs of these animals. The rat plasma soluble thrombomodulin concentrations of the different treatment groups were also evaluated. Microsomes incubation, Real Time-Polymerase Chain Reaction and Western blot was applied respectively to study the activity, mRNA expression and protein expression of CYP, VKOR and TM.ResultsThe activities and expression levels of the CYP and VKOR enzymes in the warfarin-Gegen combination groups increased by nearly 30 % (P = 0.02) compared with the warfarin-alone group, whereas those of TM decreased by almost 25 % (P = 0.02). The administration of Danshen did not lead to any changes in the activities or the expression levels of the CYP, VKOR or TM enzymes compared with those of the control group. Gegen induced several warfarin-metabolizing CYP enzymes and neutralized the effects of warfarin towards VKOR and TM.ConclusionGegen, rather than Danshen at the same tested dosage, offsets the anticoagulant effects of warfarin by accelerating the phase I liver metabolism of warfarin, as well as increasing the activity, mRNA and protein expression of VKOR while decreasing those of TM.Electronic supplementary materialThe online version of this article (doi:10.1186/s13020-016-0078-9) contains supplementary material, which is available to authorized users.
Highlights
Radix Salvia miltiorrhiza (Danshen) and Radix Puerariae lobatae (Gegen) are used in Traditional Chinese Medicine to treat cardiovascular diseases
Pharmacokinetic mechanisms of warfarin‐Gegen interaction Gegen induced the activities and mRNA expressions of different cytochrome P450 (CYP) in rat liver Induction on CYP activities for warfarin metabolism When R-warfarin was used as the substrate (5 μM), the formation of all five mono-hydroxylated warfarin metabolites in the Gegen×1 and Gegen×2 groups increased significantly by 19–31 % (P = 0.03) and 24–30 % (P = 0.03), respectively, relative to the vehicle control group
In the positive control groups, the formation of 7- and 8-hydroxylated warfarin increased by 281 % (P < 0.001) and 242 % (P < 0.001) when the animals were treated with PB and BNF [22], respectively, compared with the results of the vehicle control group (Fig. 1)
Summary
Radix Salvia miltiorrhiza (Danshen) and Radix Puerariae lobatae (Gegen) are used in Traditional Chinese Medicine to treat cardiovascular diseases. Adverse herb-drug interactions were observed between warfarin and herbal remedies containing Danshen and Gegen. The ingestion of certain plant materials such as grapefruit [6] and garlic [7, 8] can have a pronounced effect on the activity and/or expression of the CYP enzymes, which could have serious consequences for the metabolism of warfarin. The co-administration of herbs and drugs can affect the activity and expression of vitamin K epoxide reductase (VKOR), which is the target protein of warfarin in terms of its anticoagulant effects. Danshen-Gegen formula (DGF), which is a herbal medicine containing Radix Salvia miltiorrhiza (Danshen) and Radix Puerariae lobatae (Gegen), led to a 5.36-fold increase in the mRNA expression of TM [16]
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