Plasma Levels and Distribution of Flavonoids in Rat Brain After Single and Repeated Doses of Standardized Ginkgo Biloba Extract EGb 761®

It is undisputed that terpene lactones and flavonoid glycosides of Ginkgo biloba are responsible for most of the extracts (e.g., EGb 761®) pharmacological actions. This investigation focused on the pharmacokinetic and the ability of the flavonoid constituents to cross the blood-brain barrier in rats, after single (600 mg/kg) or repeated (8 days, 100, or 600 mg/kg) oral administration of EGb 761®, and their distribution in different areas of the brain. For this purpose, we developed an HPLC-fluorescence method for the determination of the Ginkgo flavonoid metabolites (quercetin, kaempferol, and isorhamnetin derivatives) in the brain and plasma. A single dose of 600 mg/kg EGb 761® resulted in maximum plasma concentrations of 176, 341, and 183 ng/mL for quercetin, kaempferol, and isorhamnetin/tamarixetin, respectively and in maximum brain concentrations of 291 ng/g protein for kaempferol and 161 ng/g protein for isorhamnetin/tamarixetin. In comparison, the repeated administration of the same dose for 8 days led to an approximate 4.5-fold increase in the plasma concentration for quercetin, 11.5-fold increase for kaempferol, and 10-fold increase for isorhamnetin/tamarixetin. In the brain, an approximate 2-fold increase was observed for kaempferol and isorhamnetin/tamarixetin. About 90% of the determined flavonoids were distributed in the hippocampus, frontal cortex, striatum, and cerebellum, which together represent only 38% of the whole brain.