Metabolism and metabolic inhibition of gambogic acid in rat liver microsomes

Aim:To study the metabolism of gambogic acid(GA)and the effects of selectivecytochrome P-450(CYP450)inhibitors on the metabolism of GA in rat liver mi-crosomes in vitro.Methods:Rat liver microsomes were used to perform metabo-lism studies.Various selective CYP450 inhibitors were used to investigate theireffects on the metabolism of GA and the principal CYP450 isofonn involved in theformation of major metabolite M1in rat liver microsomes.Types of inhibition in anenzyme kinetics model were used to model the interaction.Results:GA wasrapidly metabolized to two phase I metabolites,M1and M2,in rat liver microsomes.Ml and M2were tentatively presumed to be the hydration metabolite and epoxidemetabolite of GA,respectively,α-Naphthoflavone uncompetitively inhibited theformation of M1while ketoconazole,sulfaphenazole,diethyl dithiocarbamate andquinidine had little or no inhibitory effects on the formation of M1.Conclusion:GA is rapidly metabolized in rat liver microsomes and M1is crucial for the elimina-tion of GA.Cytochrome P-450 1A2 is the major rat CYP involved in the metabolismof GA.