Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

Aim The aim of this study was to investigate the effect of two common herbal medicines, ginkgo and ginger, on the pharmacokinetics and pharmacodynamics of warfarin and the independent effect of these herbs on clotting status. Methods This was an open label, three-way crossover randomized study in 12 healthy male subjects, who received a single 25 mg dose of warfarin alone or after 7 days pretreatment with recommended doses of ginkgo or ginger from herbal medicine products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using ANOVA and the 90% confidence intervals (CIs) of the ratio of log transformed parameters are reported. Results INR and platelet aggregation were not affected by administration of ginkgo or ginger alone. The mean (95% Cl) apparent clearances of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167-210) ml h-1, 200 (173-227) ml h-1 and 201 (171-231) ml h-1, respectively. The respective apparent clearances of R-warfarin were 127 (106-149) ml h-1, 126 (111-141) ml h-1 and 131 (106-156) ml h-1. The mean ratio (90% Cl) of apparent clearance for S-warfarin was 1.05 (0.98-1.21) and for R-warfarin was 1.00 (0.93-1.08) when coadministered with ginkgo. The mean ratio (90% Cl) of AUC0-168 of INR was 0.93 (0.81-1.05) when coadministered with ginkgo. The mean ratio (90% Cl) of apparent clearance for S-warfarin was 1.05 (0.97-1.13) and for R-warfarin was 1.02 (0.95-1.10) when coadministered with ginger. The mean ratio (90% Cl) of AUC0-168 of INR was 1.01 (0.93-1.15) when coadministered with ginger. The mean ratio (90% Cl) for S-7-hydroxywarfarin urinary excretion rate was 1.07 (0.85-1.32) for ginkgo treatment, and 1.00 (0.81-1.23) for ginger coadministration suggesting these herbs did not affect CYP2C9 activity. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin. Conclusions Ginkgo and ginger at recommended doses do not significantly affect clotting status, the pharmacokinetics or pharmacodynamics of warfarin in healthy subjects.