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Effect of Ginkgo biloba extract on oxidative metabolism of valproic acid in hepatic microsomes from donors with the CYP2C9*1/*1 genotype

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We investigated the effect of Ginkgo biloba extracts and some of its individual constituents on the oxidative metabolism of valproic acid (VPA) in hepatic microsomes from donors with the CYP2C9*1/*1 genotype. G. biloba extract decreased 4-ene-VPA, 3-OH-VPA, 4-OH-VPA, and 5-OH-VPA formation with mean(± SE) IC50 values of 340± 40μg/mL, 370± 100μg/mL, 180± 30μg/mL, and 210± 20μg/mL, respectively. This was associated with inhibition of not only CYP2C9*1, but also CYP2A6 and CYP2B6. Bilobalide, ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside, and isorhamnetin-3-O-rutinoside were not responsible for the inhibition of VPA metabolism by the extract. When analyzed as the sum of the aglycone and total glycosides present in the extract, quercetin decreased 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation by 76%, 51%, and 70%, respectively, kaempferol decreased 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation by 65%, 46%, and 49%, respectively, and isorhamnetin decreased 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation by 29%, 26%, and 31%, respectively. The 3aglycones did not affect 3-OH-VPA formation. In summary, G. biloba extract decreased hepatic microsomal formation of 4-ene-VPA, 4-OH-VPA, 5-OH-VPA, and 3-OH-VPA, but the effect was not due to the terpene trilactones or flavonol glycosides investigated in our study.

Nous avons examiné l’effet d’extraits et de quelques constituants du Ginkgo biloba sur le métabolisme oxydatif de l’acide valproïque (VPA) dans des microsomes hépatiques de donneurs ayant le génotype CYP2C9*1/*1. Un extrait de Ginkgo biloba a diminué la formation de 4-ene-VPA, 3-OH-VPA, 4-OH-VPA et 5-OH-VPA avec des valeurs de CI50 (moyenne± É-T.) de 340± 40 μg/mL, 370± 100 μg/mL, 180± 30 μg/mL et 210± 20 μg/mL respectivement. Cette diminution a été associée à l’inhibition non seulement de CYP2C9*1, mais aussi de CYP2A6 et CYP2B6. Le bilobalide, les ginkgolides A, B, C et J, la quercétine-3-O-rutinoside, le kaempférol-3-O-rutinoside et l’isorhamnétine-3-O-rutinoside n’ont pas été à l’origine de l’inhibition du métabolisme de VPA par l’extrait. Lorsque nous les avons analysés comme la somme de l’aglycone et des glycosides totaux présents dans l’extrait, la quercétine a diminué la formation de 4-ene-VPA, 4-OH-VPA et 5-OH-VPA de 76 %, 51 % et 70 % respectivement; le kaempférol de 65 %, 46 % et 49 % respectivement, et l’isorhamnétine de 29 %, 26 % et 31 % respectivement. Les 3 aglycones n’ont pas modifié la formation de 3-OH-VPA. Ainsi, l’extrait de G. biloba a diminué la formation microsomale hépatique de 4-ene-VPA, 4-OH-VPA, 5-OH-VPA et 3-OH-VPA, mais l’effet n’est pas attribuable aux trilactones terpéniques ou aux glycosides de type flavonol examinés dans notre étude.
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Document Type: Research Article

Publication date: September 1, 2007

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