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AimThe aim of this study was to investigate the effect of St John's wor t and ginseng on the pharmacokinetics and pharmacodynamics of warfarin. MethodsThis 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 14 days' pretreatment with St John's wort, or 7 days' pretreatment with ginseng. Dosing with St John's wort or ginseng 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 90% confidence intervals are reported. ResultsINR and platelet aggregation were not affected by treatment with St John's wor t or ginseng. The apparent clearances of S-warfarin after warfarin alone or with St John's wort or ginseng were, respectively, 198 ± 38 ml min -1 , 270 ± 44 ml min -1 and 220 ± 29 ml min -1 . The respective apparent clearances of R-warfarin were 110 ± 25 ml min -1 , 142 ± 29 ml min -1 and 119 ± 20 ml min -1 . The mean ratio and 90% confidence interval (CI) of apparent clearance for S-warfarin was 1.29 (1.16, 1.46) and for R-warfarin it was 1.23 (1.11, 1.37) when St John's wort was coadministered. The mean ratio and 90% CI of AUC 0 -168 of INR was 0.79 (0.70, 0.95) when St John's wort was coadministered. St John's wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers. ConclusionsSt John's wort significantly induced the apparent clearance of both S-warfarin and Rwarfarin, which in turn resulted in a significant reduction in the pharmacological effect of rac -warfarin. Coadministration of warfarin with ginseng did not affect the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin. Warfarin interaction with St John's wort and ginsengBr J Clin Pharmacol 57 :5 593

(ii) proteolysis of four out of the five enzymes in the absence of calmodulin activates their respective enzymic activities (Table 2). In fact, earlier studies revealed that Vol.

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