The effect of CTP-347 on CYP2D6-mediated tamoxifen metabolism

11552 Background: The activity of tamoxifen is primarily mediated through its 4-hydroxy metabolites which are potent antagonists of the estrogen receptor in breast tissue. The 4-hydroxylation reaction is mediated through the cytochrome P450 isozyme CYP2D6. Unfortunately, high concentrations of endoxifen, the major 4-hydroxy metabolite, have also been implicated in the occurrence of hot flashes. Although paroxetine has been demonstrated to reduce the frequency of hot flashes in investigator trials of patients with breast cancer, co- administration would reduce the effectiveness of tamoxifen since paroxetine has been shown to be a mechanism-based inactivator of CYP2D6. CTP-347 is a new chemical entity in which key hydrogen atoms of paroxetine are replaced with deuterium atoms. CTP-347 is being developed for the treatment of post-menopausal and tamoxifen-induced hot flashes and will enter clinical trials in mid-2008. Methods: Serotonin and norepinephrine reuptake inhibition was measured in rat synaptosomes u...