Metabolic interaction between biflavonoids in Ginkgo biloba leaves and tacrolimus

The aim of this study was to investigate the effect of biflavonoids in Ginkgo biloba leaves on tacrolimus metabolism. First, the inhibitory effects of five main biflavonoids (amentoflavone, sciadopitysin, ginkgetin, isoginkgetin, bilobetin) in G. biloba leaves on tacrolimus metabolism were investigated in vitro in human liver microsomes (HLM), and the concentration-dependent inhibition was further calculated. Then the time-dependent inhibition activities of five biflavonoids were studied and the drug interaction was studied in Sprague-Dawley (SD) rats. Finally, the molecular mechanism of inhibition was explored by molecular docking. The results of in vitro incubation in HLM showed tacrolimus metabolism was strongly inhibited by amentoflavone, ginkgetin, and bilobetin, whose IC₅₀ value was 5.57, 3.16, and 5.03 μM, respectively. The time-dependent inhibition of the three above biflavonoids at 50 μM was 33.47%-50.89%. In the in vivo study in rats, the AUC_0-t and C_max of tacrolimus increased 3.8-fold and 2.5-fold after oral preadministration with amentoflavone. The molecular docking results showed that the inhibitory effect may be related to the formation of hydrogen bonds. The results showed that long-term combination of G. biloba leaves and tacrolimus may cause drug-drug interactions. This study provided theoretical and experimental basis for rational drug use in clinical practice.