Herbal medicines are widely used in our community. A survey of Australian consumers indicated that 60% had used complementary and/or alternative medicines in the past year with the majority not informing their doctor that they were using herbal medicines. Little is known about the potentially serious consequences of interactions between herbal and conventional medicines. Warfarin has an important role in treating people with heart disease, yet it has a narrow therapeutic range, is highly bound to plasma proteins, and is metabolised by cytochrome P450. This creates the potential for life-threatening interactions with other drugs and foods leading to excessive bleeding. Hence, warfarin is one of the most frequently investigated drugs for interaction studies. Early clinical reports suggest that there exists the potential for an interaction between warfarin and four herbal medicines: St John�s wort, ginseng, ginkgo and ginger. However, these herb-drug combinations have never been conclusively studied. The two clinical studies conducted as part of this research had an identical study design. Twenty-four healthy male subjects were recruited into the two separate studies. This was an open label, three-way crossover randomised study in twelve healthy male subjects, who received a single 25 mg dose of warfarin alone or after 14 days pre-treatment with St John�s wort, or 7 days pre-treatment with ginseng. Dosing with St John�s wort or ginseng was continued for 7 days after administration of the warfarin dose in study I or who received a single 25 mg dose of warfarin alone or after 7 days pre-treatment with recommended doses of ginkgo or ginger from single ingredient products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose in study II. Platelet aggregation, international normalised ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured in both studies. Statistical comparisons were made using ANOVA and 95% confidence interval (CI) for mean value and 90% CI for geometric mean ratio value are reported. n study I, the mean (95% CI) apparent clearance of S-warfarin after warfarin alone or with St John�s wort or ginseng were, respectively, 198 (174 � 223) ml/h, 269 (241 � 297) ml/h and 220 (201 � 238) ml/h. The respective apparent clearances of R-warfarin were 110 (94 � 126) ml/h, 142 (123 � 161) ml/h and 119 (106 � 131) ml/h. The mean ratio of apparent clearance for S-warfarin was 1.29 (1.16-1.46) and for R-warfarin was 1.23 (1.11-1.37) when St John�s wort was co-administered. The mean ratio of AUC0-168 of INR was 0.79 (0.70 - 0.95) when St John�s wort was co-administered. The urinary excretion ratio of S-7-hydroxywarfarin after administration of warfarin alone was 0.04 (0.03 � 0.06) mg/h and there was no significant difference following treatment with either St John�s wort 0.03 (0.02 � 0.04) mg/h or ginseng 0.03 (0.02 � 0.04) mg/h. The ratio of geometric means for S-7-hydroxywarfarin UER was 0.82 (0.61-1.12) for St John�s wort, and 0.68 (0.50-0.91) for ginseng. St John�s wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers. In study II, the mean (95% CI) apparent clearance of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167 � 210) ml/h, 200 (173 � 227) ml/h and 201 (171 � 231) ml/h, respectively. The respective apparent clearances of R-warfarin were 127 (106 � 149) ml/h, 126 (111 � 141) ml/h and 131 (106 � 156) ml/h. The mean ratio of apparent clearance for S-warfarin was 1.05 (0.98 -1.12) and for R-warfarin was 1.00 (0.93 -1.08) when co-administered with ginkgo. The mean ratio of AUC0-168 of INR was 0.93 (0.81 -1.05) when co-administered with ginkgo. The mean ratio 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 co-administered with ginger. The mean ratio of AUC0-168 of INR was 1.01 (0.93 -1.15) when co-administered with ginger. The urinary excretion ratio (UER) of S-7-hydroxywarfarin after administration of warfarin alone was 0.04 (0.03 � 0.05) mg/h and there was no significant difference following treatment with either ginkgo 0.04 (0.03 � 0.04) mg/h or ginger 0.03 (0.02 � 0.04) mg/h. The ratio of geometric means for S-7-hydroxywarfarin UER was 1.07 (0.69-1.67) for ginkgo, and 1.00 (0.64-1.56) for ginger. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin. In conclusion, St John�s wort significantly induced the apparent clearance of both S-warfarin and R-warfarin, which in turn resulted in a significant reduction in the pharmacological effect of rac-warfarin. Ginseng, ginkgo and ginger at recommended doses affect neither clotting status, nor the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin in healthy subjects
