Interaction of Abiraterone and Its Pharmacologically Active Metabolite D4A with Cytochrome P450 2C9 (CYP2C9)

We studied the interaction of the antitumor agent abiraterone and its pharmacologically active metabolite D4A, which is promising for use as an agent for the treatment of prostate cancer, with cytochrome P450 2C9 (CYP2C9). Using the absorption spectroscopy, it has been shown that both compounds under study cause spectral changes of CYP2C9, indicating the interaction of the nitrogen atom of the pyridine ring of the ligand with the heme iron ion of the active site of the enzyme. However, the ligand-enzyme interaction, which is mediated by water bound to the heme iron ion, is possible. Based on the spectral changes, the values of dissociation constants (K-S) of the complexes of abiraterone and D4A with CYP2C9 were determined, which amounted to 1.73 +/- 0.14 mu M and 3.95 +/- 0.16 mu M, respectively. Both compounds inhibited the O-demethylase activity of CYP2C9 toward the substrate of this enzyme, naproxen. At a naproxen concentration of 100 mu M, the concentrations of abiraterone, D4A, and sulfaphenazole, which inhibit CYP2C9 activity by 50% (IC50), were determined as 13.9 mu M, 40 mu M, and 41 mu M, respectively. The data obtained can be used to predict drug-drug interactions at the CYP2C9 level when using abiraterone or D4A as an antitumor agent for the treatment of prostate cancer in complex pharmacotherapy.