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The effect of Ginkgo Biloba extract on valproic acid metabolism by human liver microsomes from donors with the CYP2C9*1/*1 genotype Numa, Andres Masato

Abstract

Ginkgo biloba extract (GBE) is a popular herbal preparation used primarily in the treatment of dementia, peripheral vascular diseases, and neurosensory problems. In this study, the effect of GBE on the oxidative metabolism of the anti-epileptic valproic acid (VPA) was investigated. Human liver microsomes (HLM) from donors with the CYP2C9*1/*1 genotype were incubated with VPA and GBE, and the formation of 4-ene-VPA, 4-OH-VPA, 5-OH-VPA, and 3-OH-VPA were monitored by GC/MS in NICI mode. GBE inhibited the formation of all four metabolites in a dose-dependent manner. GBE from three different sources showed similar inhibition of metabolite formation. Pre-incubation of H LM with a monoclonal antibody against CYP2C9 significantly reduced the formation of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA, demonstrating that CYP2C9 is the major isoform responsible for their formation. Pre-incubation of H L M with monoclonal antibodies against CYP2B6 and CYP2A6 reduced their formation by a smaller amount, suggesting that they are minor isoforms involved in their formation. Pre-incubation of H LM with monoclonal antibodies against CYP2B6 and CYP2A6 followed by incubation with VPA and GBE dramatically reduced their formation. These results show that the inhibition of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation in H LM by GBE is due mostly to inhibition of CYP2C9. These results were confirmed by incubations with recombinant enzymes. GBE inhibited 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation by recombinant CYP2C9; 4-ene-VPA, 4- OH-VPA, and 5-OH-VPA formation by recombinant CYP2B6; and 3-OH-VPA formation by recombinant CYP2A6. To elucidate which constituents of GBE are responsible for the inhibition seen with the whole extract, individual terpene trilactones (bilobalide and ginkgolides A, B, C, and J) and flavonol glycosides (isorhamnetin-3-O-nitinoside, kaempferol-3-O-rutinoside, and quercetin-3- O-rutinoside) were incubated with VP A. However, at the concentrations present in GBE, these constituents failed to inhibit VPA metabolism. The aglycones of isorhamnetin, kaempferol, and quercetin inhibited VPA metabolism. Although the aglycones were not detected in GBE, they may be of importance in vivo, as flavonol glycosides are hydrolyzed to their respective aglycones in the small intestine. In conclusion, GBE inhibited the CYP2C9-, CYP2B6-, and CYP2A6-mediated metabolism of VPA. However, the effect could not be explained by the individual terpene trilactones or flavonol glycosides tested.

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