In vitro interactions of abiraterone, erythromycin, and CYP3A4: implications for drug–drug interactions.

Masamrekh, Rami A.; Kuzikov, Alexey V.; Haurychenka, Yaraslau I.; Shcherbakov, Kirill A.; Veselovsky, Alexander V.; Filimonov, Dmitrii A.; Dmitriev, Alexander V.; Zavialova, Maria G.; Gilep, Andrei A.; Shkel, Tatsiana V.; Strushkevich, Natallia V.; Usanov, Sergey A.; Archakov, Alexander I.; Shumyantseva, Victoria V.

Potential drug–drug interactions of the antitumor drug abiraterone and the macrolide antibiotic erythromycin were studied at the stage of cytochrome P450 3A4 (CYP3A4) biotransformation. Using differential spectroscopy, we have shown that abiraterone is a type II ligand of CYP3A4. The dependence of CYP3A4 spectral changes on the concentration of abiraterone is sigmoidal, which indicates cooperative interactions of CYP3A4 with abiraterone; these interactions were confirmed by molecular docking. The dissociation constant (Kd) and Hill coefficient (h) values for the CYP3A4–abiraterone complex were calculated as 3.8 ± 0.1 μM and 2.3 ± 0.2, respectively. An electrochemical enzymatic system based on CYP3A4 immobilized on a screen‐printed electrode was used to show that abiraterone acts as a competitive inhibitor toward erythromycin N‐demethylase activity of CYP3A4 (apparent Ki = 8.1 ± 1.2 μM), while erythromycin and its products of enzymatic metabolism do not affect abiraterone N‐oxidation by CYP3A4. In conclusion, the inhibition properties of abiraterone toward CYP3A4‐dependent N‐demethylation of erythromycin and the biologically inert behavior of erythromycin toward abiraterone hydroxylation were demonstrated.

ERYTHROMYCIN; MACROLIDE antibiotics; CYTOCHROME P-450; ANTINEOPLASTIC agents; DRUG interactions; MOLECULAR docking; CLARITHROMYCIN; ENZYMATIC analysis

Fundamental & Clinical Pharmacology, 2020, Vol 34, Issue 1, p120

0767-3981

Academic Journal

10.1111/fcp.12497