Impact of Metabolizing Enzymes on Drug Response of Endocrine Therapy in Breast Cancer

Pilar H Saladores; Jana C Precht; Werner Schroth; Hiltrud Brauch; Matthias Schwab

Disclosures

Expert Rev Mol Diagn. 2013;13(4):349-65. 

In This Article

Phenocopying of CYP2D6

Currently, the American Society of Clinical Oncology (ASCO) recommends using caution when CYP2D6 inhibitors are coadministered throughout the duration of tamoxifen treatment.[8] Potent inhibitors of CYP2D6 reduce its enzymatic function, resulting in a change of phenotype of EM to PM in the most extreme case, known as phenocopying.[45,46] Thus, drug interactions of potent inhibitors are a major confounding factor of the CYP2D6 phenotype. Known CYP2D6 inhibitors predominantly used in breast cancer patients are selective serotonin reuptake inhibitors (SSRIs) given to overcome tamoxifen side effects like hot flashes as a consequence of antiestrogen action.[47] The potency of SSRIs to inhibit CYP2D6-catalyzed oxidation of sparteine has been analyzed using human liver microsomes.[48] Inhibition constants (Ki) for various SSRIs are in descending order: fluvoxamine (8.2 µM), citalopram (5.1 µM), sertraline (0.70 µM), fluoxetine (0.60 µM) and paroxetine (0.15 µM), indicating that paroxetine is the strongest inhibitor. Several pharmacokinetic studies evaluated the effect of SSRIs on tamoxifen metabolism and showed that coadministration of paroxetine substantially reduced the level of plasma endoxifen concentrations.[30,47,49] CYP2D6 inhibitor use impairs tamoxifen metabolism and potentially diminishes the clinical efficacy toward an inferior outcome.[50] Notably, comedication with paroxetine during tamoxifen treatment was shown to raise the risk of death from breast cancer.[51] By contrast, the antidepressant venlafaxine, a serotonin–norepinephrine reuptake inhibitor, is a very weak CYP2D6 inhibitor.[52] The Ki value of venlafaxine, as determined by dextromethorphan O-demethylation, is 33 µM, which is one to three orders of magnitude larger compared with SSRIs including paroxetine, norfluoxetine, sertraline and fluvoxamine.[53] Interestingly, venlafaxine use did not change breast cancer mortality with concomitant tamoxifen treatment.[51] Altogether, these findings have strengthened the argument against the practice of coadministration of potent CYP2D6 inhibitors with tamoxifen treatment. The concept of drug–drug interaction between potent CYP2D6 inhibitors and tamoxifen resulting in worse outcome in postmenopausal women strongly supports an important role of CYP2D6 on tamoxifen efficacy.

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