title: Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo.
abstract: 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 microg/mL, and the inhibition was increased by acid hydrolysis (apparent Ki=9.1 microg/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.
authors.affiliation: Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mohutsky
authors.forename: Gail D
authors.initials: GD
authors.lastname: Anderson
authors.forename: John W
authors.initials: JW
authors.lastname: Miller
authors.forename: Gary W
authors.initials: GW
authors.lastname: Elmer
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D065729:Cytochrome P-450 CYP2C9; D004008:Diclofenac / Q000493:pharmacokinetics*; D004357:Drug Synergism; D005260:Female; D020441:Ginkgo biloba; D041743:Herb-Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010936:Plant Extracts / Q000493:pharmacokinetics; D014044:Tolbutamide / Q000493:pharmacokinetics*
chemical_list: D010936:Plant Extracts; D004008:Diclofenac; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases