Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects

Abstract

Background and purpose: Patients commonly take complementary medicines in conjunction with warfarin yet evidence supporting the safety or the risk of a herb-drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects.

Experimental approach: An open-label, three-treatment, randomized crossover clinical trial was undertaken and involved 12 healthy male subjects of known CYP2C9 and VKORC1 genotype. A single dose of 25 mg warfarin was administered alone or after 2 weeks of pretreatment with either garlic or cranberry. Warfarin enantiomer concentrations, INR, platelet aggregation and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions between warfarin and herbal medicines.

Key results: Cranberry significantly increased the area under the INR-time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S- or R-warfarin pharmacokinetics or plasma protein binding. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin, which is worthy of further investigation.

Conclusions and implications: Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly. Co-administration of warfarin and cranberry requires careful monitoring.

Figure 1

International normalized ratio of prothrombin time (INR) vs time profile (n=12) after a single oral dose of warfarin (25 mg) alone, and after multiple dose of cranberry juice concentrate capsules and after multiple dose of enteric-coated garlic tablets.

Figure 2

Individual area under the international normalized ratio (INR)–time curve (AUC_INR) of subjects receiving warfarin alone or after pretreatment with cranberry. A majority of subjects showed a tendency towards an increase in AUC_INR following cranberry and warfarin treatment in comparison with warfarin alone. However, two subjects exhibited a decrease in AUC_INR.

Figure 3

Percentage clotting activity vs midpoint time profiles for (a) Factor II, (b) Factor VII and (c) Factor X during warfarin treatment alone or after cranberry pretreatment. Mean and s.d. (error bars) are presented.

Figure 4

Plasma concentration–time profile of (a) S-warfarin and (b) R-warfarin after a single oral dose of warfarin (25 mg) alone, or after multiple doses of cranberry juice concentrate capsules given along with single dose of warfarin and after multiple doses of enteric-coated garlic tablets.