Endoxifen, the Active Metabolite of Tamoxifen, Is a Substrate of the Efflux Transporter P-Glycoprotein (Multidrug Resistance 1)

Abstract

ABSTRACT:Tamoxifen is widely prescribed to patients with estrogen receptor-positive breast cancer, and it is a prodrug that requires bioactivation by cytochrome P450 enzymes CYP2D6 and 3A4 to generate the active metabolite, endoxifen. Large interpatient variability in endoxifen plasma levels has been reported, and polymorphisms in CYP2D6 have been implicated as a major determinant of such variability. However, little is known regarding the role of drug transporters such as P-glycoprotein [multidrug resistance 1 (MDR1), ATP-binding cassette B1 (ABCB1)] to endoxifen disposition and response. Therefore, we determined the ability of P-glycoprotein to transport endoxifen in vitro, using a polarized human P-glycoprotein-overexpressing cell line. Markedly higher transport of endoxifen was observed in the basal-to-apical direction, which was abrogated in the presence of the potent and specific P-glycoprotein inhibitor (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (LY335979). To validate the in vivo relevance of P-glycoprotein to endoxifen disposition, plasma and tissue concentrations were also determined in Mdr1a-deficient mice after oral administration of endoxifen. Plasma endoxifen levels did not significantly differ between wild-type and Mdr1a-deficient mice. However, brain concentrations of endoxifen were nearly 20-fold higher in Mdr1a-deficient mice compared to wild-type mice. Because Pglycoprotein is highly expressed at the blood-brain barrier and in some breast cancer tumors, variation in expression and function of this transporter may alter central nervous system entry and the attained intracellular concentration in such breast cancer cells and therefore may prove to be of relevance to therapeutic outcome.

The Risk of Recurrence in Breast Cancer Patients Treated with Tamoxifen: Polymorphisms of CYP2D6 and ABCB1

“…Substitution of these nucleotides results in change of a lipophilic residue to a hydrophilic one and affects the geometric precision of the interaction site and the secondary structure (20). Tamoxifen, 4-hydroxytamoxifen and endoxifen are known to bind P-gp and are substrates of P-gp which may acts as a barrier and limits the accessibility of active metabolites of tamoxifen to various critical target tissues and the success of tamoxifen therapy (21,22). P-gp expression was also found to increase from 40-50% to 60-70% after chemotherapy in breast cancer patients and resulted in a shorter overall survival in patients (21).…”

Rethinking tamoxifen in the management of melanoma: New answers for an old question

“…Tamoxifen and its metabolites bind P-glycoprotein, which may decrease their access to target tissues (Teft et al, 2011;Teh et al, 2012). Interestingly, patients having both CYP2D6 intermediate metabolizers and CC genotype of ABCB1 have shorter recurrence-free rates as compared with patients carrying only one of them (Teh et al, 2012), suggesting that the monitoring of ABCB1 genotype may be important as well.…”

Contribution of ABCB1 gene polymorphisms to breast cancer cells response to chemotherapy

“…Opisano 11 transkryptów tego genu [15] i udowodniono, że w regulacji transkrypcji mogą brać udział obydwa promotory. W rejonie genu ABCB1 zidentyfikowano 3523 polimorfizmy, z czego znaczącą większość stanowią polimorfizmy pojedynczego nukleotydu (single nucleotide polymorphism -SNP) występujące w egzonach, intronach oraz w obszarach nieTabela I. Substraty oraz inhibitory glikoproteiny P (wg [20], [44], zmodyfikowano). Zestawienie przykładowych, powszechnie stosowanych leków będących modulatorami aktywności glikoproteiny P Częstość występowania tych polimorfizmów zależy od badanej populacji, np.…”

“…Niestety, ok. 40-50% chorych z dodatnim statusem ER (receptor estrogenowy, estrogen receptor) nie odpowiada na terapię tym lekiem [33]. Może to być wynikiem zwiększonego usuwania endoksifenu (aktywnego metabolitu tamoksifenu) przez glikoproteinę P, której aktywność wzrasta po ekspozycji na tamoksifen [44]. Efekt ten może być modyfikowany przez obecność polimorfizmów genu ABCB1.…”