Comparative metabolic study between two selective estrogen receptor modulators, toremifene and tamoxifen, in human liver microsomes.
Drug Metab Pharmacokinet
; 30(5): 325-33, 2015 Oct.
Article
en En
| MEDLINE
| ID: mdl-26423799
ABSTRACT
Toremifene (TOR) and Tamoxifen (TAM) are widely used as endocrine therapy for estrogen receptor positive breast cancer. Poor metabolizers of TAM are likely to have worse clinical outcomes than patients who exhibit normal TAM metabolism due to lower plasma level of its active metabolite, 4-hydroxy-N-desmethyl (4OH-NDM) tamoxifen (endoxifen). In this study, we examined the role of individual cytochrome P450 (CYP) isoforms in the metabolism of TOR to N-desmethyl (NDM), 4-hydroxy (4OH) and 4OH-NDM metabolites in comparison with TAM using human liver microsomes (HLMs) with selective chemical inhibitors for each CYP isoform and recombinant CYP proteins. Similar levels of NDM metabolites were formed for both TOR and TAM, and N-demethylation of both compounds was primarily carried out by CYP3A4. We found that the formation of 4OH-NDM-TOR was catalyzed both by CYP2C9 and CYP2D6, whereas the formation of 4OH-TAM and endoxifen was specifically catalyzed by CYP2D6 in HLMs. Our results suggest that the potential contribution of CYP2D6 in the bioactivation pathway of TOR may be lower compared to TAM, and may have a different impact on clinical outcome than CYP2D6 polymorphisms.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Tamoxifeno
/
Microsomas Hepáticos
/
Toremifeno
/
Moduladores Selectivos de los Receptores de Estrógeno
Límite:
Female
/
Humans
Idioma:
En
Revista:
Drug Metab Pharmacokinet
Asunto de la revista:
FARMACOLOGIA
/
METABOLISMO
Año:
2015
Tipo del documento:
Article