Ginkgo biloba extract is one of the most widely used herbal products in the United States. However, bleeding episodes in patients taking Ginkgo biloba and warfarin have been documented. Therefore, in vitro and in vivo inhibition studies were done to ascertain the influence of ginkgo on CYP2C9, the P-450 isozyme responsible for the metabolism of the most potent warfarin enantiomer, (S)-warfarin. Ginkgo extract inhibited human liver microsomal CYP2C9 with an apparent Ki =14.8 μg/mL, and the inhibition was increased by acid hydrolysis (apparent Ki = 9.1 μg/mL). Two open-label, crossover pharmacokinetic studies in healthy subjects were performed using tolbutamide and diclofenac as probe CYP2C9 substrates. In contrast to the in vitro inhibition of CYP2C9, no interactions between Ginkgo biloba extract and CYP2C9 probe substrates were observed in vivo as evidenced by the lack of effect on the steady-state pharmacokinetics of diclofenac or on the urinary metabolic ratio of tolbutamide.
1Department of Medicinal Chemistry, University of Washington, Seattle, Washington; 2Department of Pharmacy, University of Washington, Seattle, Washington; and 3Department of Neurology and Neurological Surgery, University of Washington, Seattle, Washington.
*Address for correspondence: Department of Medicinal Chemistry, Box 357610, University of Washington, Seattle, WA 98195. E-mail: email@example.com
Dr. Mohutsky is currently with Lilly Research Laboratories, Department of Drug Disposition, Eli Lilly and Company, Indianapolis, IN 46285.
Supported by grants from the Royalty Research Fund, University of Washington, and National Institutes of Health Research Service Award GM07750-24. We also acknowledge support from the Geraldine Brady Grant for Support for Faculty Research on Natural Products. A portion of this work was conducted through the Clinical Research Center Facility at the University of Washington and supported by the National Institutes of Health grant M01-RR-00037.