Acta Pharmacologica Sinica 2006 September; 27 (9): 1253-1258; doi: 10.1111/j.1745-7254.2006.00369.x

Aim: To study the metabolism of gambogic acid (GA) and the effects of selective cytochrome P-450 (CYP450) inhibitors on the metabolism of GA in rat liver microsomes in vitro.

Methods: Rat liver microsomes were used to perform metabolism studies. Various selective CYP450 inhibitors were used to investigate their effects on the metabolism of GA and the principal CYP450 isoform involved in the formation of major metabolite M₁ in rat liver microsomes. Types of inhibition in an enzyme kinetics model were used to model the interaction.

Results: GA was rapidly metabolized to two phase I metabolites, M₁ and M₂, in rat liver microsomes. M₁ and M₂ were tentatively presumed to be the hydration metabolite and epoxide metabolite of GA, respectively. α-Naphthoflavone uncompetitively inhibited the formation of M₁ while ketoconazole, sulfaphenazole, diethyl dithiocarbamate and quinidine had little or no inhibitory effects on the formation of M₁.

Conclusion: GA is rapidly metabolized in rat liver microsomes and M₁ is crucial for the elimination of GA. Cytochrome P-450 1A2 is the major rat CYP involved in the metabolism of GA.

Keywords: gambogic acid; metabolism; cytochrome P-450; liver microsomes; metabolic inhibition