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


METHODS
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.


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
Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly. Co-administration of warfarin and cranberry requires careful monitoring.
Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia.
M I
MI
Mohammed Abdul
X
X
Jiang
K M
KM
Williams
R O
RO
Day
B D
BD
Roufogalis
W S
WS
Liauw
H
H
Xu
A J
AJ
McLachlan
D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D016903:Drug Monitoring; D005737:Garlic / Q000737:chemistry*; D005838:Genotype; D041743:Herb-Drug Interactions; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics; D010974:Platelet Aggregation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D013237:Stereoisomerism; D013997:Time Factors; D029799:Vaccinium macrocarpon / Q000737:chemistry*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000493:pharmacokinetics / Q000494:pharmacology*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases