Exemestane is metabolized by the liver enzyme CYP3A4. While the CYP3A4 inhibitor ketoconazole had no significant effect on exemestane levels in a clinical trial, the strong CYP3A4 inductor rifampicin significantly cut exemenstane levels about in half (AUC −54%, C −41% for a single dose), potentially compromising its effectiveness. Other 3A4 inductors such as carbamazepine and St John's Wort are expected to have similar effects. The clinical relevance of this effect has not been investigated.
Estrogens probably reduce exemestane effectiveness: It would usually be counter-productive to reduce the body's estrogen synthesis with exemestane and then substitute estrogen with pharmaceuticals.