Inhibition of intestinal and hepatic glucuronidation of mycophenolic acid by Ginkgo biloba extract and flavonoids.

Herb-drug interactions have received more attention in recent years because of the widespread popularity of herbal supplements. However, there are limited data on the effect of herbs on glucuronidation in humans. The goal of this work was to examine the effect of Ginkgo biloba extract and its main flavonoid and terpene lactone constituents on mycophenolic acid (MPA) 7-O-glucuronidation. Human liver (HLM) and intestinal (HIM) microsomes were incubated with MPA and G. biloba extract (unhydrolyzed or acid-hydrolyzed), quercetin, kaempferol, ginkgolide A, ginkgolide B, or bilobalide. MPA-7-O-glucuronide formation was inhibited in HLM and HIM incubations by unhydrolyzed [IC(50) = 84.3 (HLM) and 6.9 (HIM) microg/ml] and hydrolyzed [IC(50) = 20.9 (HLM) and 4.3 (HIM) microg/ml] G. biloba extracts, quercetin [IC(50) = 19.1 (HLM) and 5.8 (HIM) microM], and kaempferol [IC(50) = 23.1 (HLM) and 7.7 (HIM) microM]. Terpene lactones did not show inhibition of MPA glucuronidation. Quercetin was a mixed-type inhibitor in HLM and HIM incubations [K(i) = 11.3 (HLM) and 2.8 (HLM) microM], whereas kaempferol was a noncompetitive inhibitor in HLM (K(i) = 33.7 microM) and a mixed-type inhibitor in HIM (K(i) = 4.5 microM). These results indicate that G. biloba extract or quercetin- and kaempferol-rich supplements may inhibit intestinal and hepatic glucuronidation of MPA. Future studies are needed to evaluate the clinical significance of this interaction.