Zytiga Inhibits CYP2D6 Metabolism of Dextromethorphan

Zyiga is the trade name for Abiraterone Acetate. Once absorbed by the body this prodrug is cleaved by plasma esterases in the bloodstream to liberate free Abiraterone which inhibits the CYP17 enzyme in tumours to stop all androgen production and switches off testosterone biosynthesis. Abiraterone has been designed as a very potent and selective inhibitor of CYP17 and does not inhibit closely related CYP enzymes such as CYP19 which is used for comparison.

However during clinical development it was found that Abiraterone also inhibited the liver enzyme CYP2D6. This has important implications for drugs that are activated or deactivated by CYP2D6. Dextromethorphan is a substrate for CYP2D6 and its metabolism has been studied clinicaly in the presence of Zytiga which showed an increase in the concentration curve of Dextromethorphan showing that Zytiga decreases the metabolism of this drug and leads to prolonged Dextromethorphan exposure.

Tamoxifen is activated to its 4-hydroxy metabolite 4-hydroxy tamoxifen by CYP2D6 which is thought to be the active antiestrogenic metabolite. Tamoxifen is also N-demthylated by CYP2D6 so this enzyme plays an important role in Tamoxifen metabolism. Zytiga is undergoing clinical trials against advanced breast cancer and so its effects on decreasing CYP2D6 mediated metabolism should be taken into account. The predictions are that Zytiga will inhibit CYP2D6 and decrease the amount of 4-hydroxy tamoxifen formed and therefore Zytiga will decrease the activity of Tamoxifen.