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- Materials and methods
The anticoagulant warfarin is a commonly prescribed medication which has a narrow therapeutic index and displays high inter- and intrasubject variability in response. In the community there is also widespread, often unreported, self-medication with a range of herbal medicines. The opportunity for potentially life-threatening interactions between herbal medications and warfarin is thus high . Ginkgo (Ginkgo biloba) is one such herbal medicine which is commonly used as the ginkgo extract EGb 761 for promoting and maintaining mental alertness, concentration and focus as well as for a wide range of other indications [2, 3]. However, relatively little is know about ginkgo–drug interactions. A recent review article  identified one case report of an interaction between ginkgo and warfarin and four case reports of spontaneous bleeding associated with the use of ginkgo alone attributed to possible effects on platelet function. In vitro studies indicate that constituents of Ginkgo biloba (ginkgolic acids I and II) inhibit drug metabolizing enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 . In contrast, administration of ginkgo extracts to rats for 4 weeks reportedly reduced the hypotensive effect of nicardipine (which is metabolized by CYP3A2) and induced hepatic CYP2B1/2, CYP3A1 and CYP3A2 mRNA . In vitro animal and in vivo clinical studies have investigated the effect of ginkgo extracts on platelet aggregation and coagulation, but the results have been conflicting [6–9].
Ginger (Zingiber officinale) is a herbal medicine taken for a variety of indications including the symptomatic relief of motion sickness and inflammation , but few drug interaction studies have been undertaken with this herb. Several in vitro studies have demonstrated that platelet aggregation is inhibited by ginger extracts [11–15]. Furthermore, a single dose (10 g) of powdered ginger inhibited platelet aggregation in patients .
The aim of the present study was to investigate the possible herb–drug interactions between warfarin and these two widely used herbal medicines and their independent effects on clotting status.
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- Materials and methods
Co-administration of recommended doses of two commonly used herbal medicines, ginkgo and ginger, did not affect the pharmacokinetics nor the pharmacodynamics of warfarin enantiomers after a single dose of warfarin in healthy male subjects. Furthermore, these herbal medicines did not have an independent effect on blood clotting status or platelet aggregation.
The herbal medicine products of known quality were selected for use in this study and the doses in which they were administered conformed to the recommendations in the Herbal Medicine-Expanded Commission E Monographs. In evaluating the composition of different commercial herbal medicine products we found that products containing ginkgo were qualitatively similar, however, there was notable variability in the composition of the different products containing ginger. This observation reinforces the need to establish the quality of herbal medicine products used in clinical studies. The ginkgo product chosen for the present study (Tavonin™) contained the standardized Ginkgo biloba extract, EGb 761 which has been investigated in numerous clinical trials and has been the subject of a Cochrane Database systematic review . However, it cannot necessarily be assumed that similar findings would result from similar studies of other commercial sources of these extracts. This represents one of the difficulties in studying and interpreting the results of this complex area.
The anticoagulant activity of S-warfarin is several-fold greater than that of the R-enantiomer . Elucidation of the pharmacokinetics of the individual warfarin enantiomers allows an assessment of the possible mechanisms involved in herb–drug interactions. S-warfarin is predominantly metabolized to S-7-hydroxywarfarin by CYP2C9 [21, 22] while R-warfarin is partly metabolized to 6- and 8-hydroxywarfarin by CYP1A2 and to 10-hydroxywarfarin by CYP3A4 [23, 24]. The baseline pharmacokinetic parameters of the enantiomers of warfarin were in agreement with those reported previously [17, 25].
This study used a single 25 mg dose and a cross-over design to investigate possible herb–drug interactions. This design has been safely used by many researchers to investigate potential drug–drug interactions with warfarin and with appropriate sampling this approach allows insight into the possible mechanisms of warfarin drug interactions. A single 25 mg dose of warfarin was used because it induces a significant change in INR from baseline (i.e. maximum INR was approximately 2.5) which allows assessment of the possible additive or reductive effects of coadministration of herbs on warfarin's response. One possibility is that a large dose of warfarin would mean that the maximum pharmacodynamic response is achieved and that amplification of warfarin-induced anticoagulation might not be detected. However, Chan et al. used a combined pharmacokinetic–pharmacodynamic (PK/PD) modelling approach to show that this study design could detect interactions that both increased and decreased INR from the control. Furthermore, in a preliminary analysis using the modelling approach described by Chan et al. we found that only about 80% of the maximum effect of warfarin anticoagulant response was achieved after a single 25 mg dose of warfarin which suggests the study design was sensitive enough to detect both an increase and decrease in INR. This consideration is important given that this study did not detect a significant change in warfarin response when coadministered with either gingko or garlic.
While no interaction was observed between warfarin and ginkgo in this study, ginkgo constituents have been reported to both inhibit and, paradoxically, induce cytochrome P450, depending on the study design [4, 5, 26]. Gurley et al. reported that ginkgo extract (60 mg, 4× day−1 for 28 days) administration to healthy subjects caused no alteration in the activities of CYP3A4, CYP1A2, CYP2E1 or CYP2D6 assessed using a cocktail of specific substrates for individual cytochromes (note: CYP2C9 activity was not investigated). Recently, the effect of ginkgo coadministration on warfarin pharmacodynamics (INR) was investigated using a randomized, double-blind placebo-controlled cross-over trial in patients taking 100 mg of ginkgo extract daily for 4 weeks. These researchers concluded that ginkgo did not influence warfarin response at this dose , but the effect of ginkgo on the pharmacokinetics of warfarin enantiomers was not investigated. In the present study, recommended doses of ginkgo did not affect the apparent clearance of warfarin enantiomers, which suggests that this herb (at this dose) does not significantly influence CYP1A2, CYP3A4 and CYP2C9 activity. The finding that S-7-hydroxywarfarin urinary excretion rate was unaltered by ginkgo (and ginger) supports the observation that ginkgo (and ginger) did not affect CYP2C9 activity. The conflicting observations regarding the possible effects of ginkgo constituents on cytochrome P450 could be a consequence of variability in the concentration of different constituents of ginkgo used in different studies. For example, the EGb 761 extract contains less than 5 p.p.m. ginkgolic acid, a constituent known to influence CYP activity in vitro[4, 25].
Several in vitro studies have demonstrated that ginkgo constituents (including ginkgolides) could inhibit platelet activating factor (PAF) but not adenosine diphosphate (ADP) or arachidonic acid induced platelet aggregation [8, 29–31]. Furthermore, collagen induced platelet aggregation was inhibited after an infusion of a ginkgo extract to patients with arteriosclerosis . Similarly, ginkgo extract significantly reduced collagen but not PAF-mediated platelet aggregation in healthy subjects, and in type 2 diabetic subjects who ingested 120 mg of a standardized ginkgo extract for 3 months . However, there is also evidence to suggest that ginkgo does not affect ADP or collagen-induced platelet aggregation in vitro in rats . In a prospective double-blind, randomized placebo-controlled study in healthy subjects, ginkgo extract did not alter platelet activity or coagulation using three different doses (120, 240 and 480 mg day−1) for 14 days  which is consistent with the finding of the present study in healthy subjects.
Few ginger–drug interactions have been reported in the literature. A series of synthetic gingerols and phenylalkanol analogues were found to inhibit arachidonic acid induced platelet serotonin release and aggregation based on an in vitro study in human blood . Furthermore, ginger extracts have been reported to inhibit platelet aggregation induced by arachidonic acid, epinephrine, ADP or collagen based on in vitro studies [12–15]. However, in vivo, no significant effect on coagulation or on warfarin response was found in the rat following multiple 100 mg kg−1 doses of ginger extract . There is conflicting evidence related to the effect of ginger constituents on human platelets suggesting that recommended doses (less than 5 g) of ginger do not affect platelet aggregation [16, 35, 36]. In the present study, no significant effect was found on platelet aggregation and coagulation in healthy human subjects who received a daily dose of 3.6 g of ginger for 5 days.
It is not surprising that there are conflicting results of the effects of ginger and ginkgo on clotting status, and on the pharmacokinetics and pharmacodynamics of warfarin, and for herbal drug interactions in general. There is a range of uncontrolled variables across different studies (including differences in the amounts and proportions of constituents in the herbal products depending on their source and preparation) as well as recognized known differences (including aspects of the study design, study population, species differences, variable dosing regimens) . Nevertheless, in the present study we have attempted to control some of these variables and reflect ‘common recommended practice’ by using a standard study design and herbal medicine products of known quality at recommended doses.
In summary, neither ginkgo nor ginger administered in herbal medicine products at recommended doses were found to affect the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin in humans, nor did they affect coagulation status. These findings suggest that the coadministration of ginkgo or ginger at recommended doses is unlikely to cause problems in healthy persons which is consistent with recent controlled trials in the literature. The significance of herb–drug interactions in elderly patients receiving warfarin or in patients taking higher than recommended doses or combinations of these herbal medicines has yet to be established.