Endoxifen

LC/tandem MS assays for tamoxifen metabolites have been described by numerous investigators and used for research purposes [10-12], Figure 1 shows a typical chromatogram for the analyses of these metabolites from a serum sample. Following chronic administration of a standard 20 mg tamoxifen per day dosage on presumably wild-type subjects, typical serum concentrations at steady state were 150 ( 50)ng/mL for tamoxifen, 180 ( 70)ng/mL for /V-desmethytam, 2.5 ( 1.2)ng/mL for 4-hydroxytam, and 5.0 ( 2.5)ng/mL for endoxifen [10],... 

Fig. 1 Representative chromatograms of the LC/MS/MS analysis of tamoxifen and its principal metabolites from serum of a patient with breast cancer. EM, IM, PM, extensive, intermediate, and poor metabolizers, respectively, for 2D6. TDM, therapeutic drug monitoring. Tamoxifen 205 ng/mL, endoxifen 32.8 ng/mL, iV-desmethyl tamoxefin 320 ng/mL, 4-ohydroxytamoxefm 5.6 ng/mL...

Of these active metabolites, endoxifen is suggested to be the primary active metabolite responsible for the majority of tamoxifen clinical efficacy, as endoxifen plasma concentrations are about five to tenfold higher than those of 4-hydroxy-tamoxifen [11, 165], Endoxifen may have additional mechanisms of action than 4-hydroxy-tamoxifen by targeting Era for degradation by proteasome [166] and through the promotion of ERa/ERf) heterodimerization, blocking ERa transcriptional activity [167],... 

Fig. 2 Principal tamoxifen metabolic pathways of clinical interest. Abbreviations Tam (Tamoxifen), A -D- iam (A-desmethyl-tamoxifen), (V-DD-Tam (/V,(V-didesmethyl-tamoxifen), 4-OH-Tam (4-Hydroxy-Tamoxifen), 4 -OH-Tam (4 -Hydroxy-tamoxifen), Tam-NO (Tamoxifen-lV-oxide), Endoxifen (4-Hydroxy-A-desmethyl-tamoxifen), 4 -OH-iV-D-Tam (4 -Hydroxy-(V-desmethyl-tamoxifen), Tam-A -Gluc (Tamoxifen-A -glucuronide), Tam-4-O-Gluc (Tamoxifen-4-O-glucuronide), A-D-Tam-4-O-Gluc (iV-desmethyl-tamoxifen-4-O-glucuronide), Tam-4-0-S03H (Tamoxifen-4-O-sulfate), A-D-Tam-4-0-S03H (iV-desmethyl-tamoxifen-4-O-sulfate)...

Briefly, tamoxifen is primarily oxidized to /V- de s i n e t h y I - tamoxifen (the most abundant metabolite in human plasma) and 4-hydroxy-tamoxifen predominantly by CYP3A4/5 and CYP2D6, respectively, followed by endoxifen formation from A-desmethyl-tamoxifen, exclusively catalyzed by CYP2D6 and from 4-hydroxy-tamoxifen by CYP3A4/5 (Fig. 2). 

Despite the obvious benefits of this drug in the different treatment settings, the clinical outcomes of tamoxifen treatment in terms of efficacy and side effects are incomplete and inconstant, and almost 30-50 % of patients either fail to respond or become resistant to tamoxifen [188], One of the proposed mechanisms that may account for the impaired response to tamoxifen therapy is an altered bioactivation of the parent drug into endoxifen, either by genetic or environmental factors [188, 189],... 

Actually, CY2D6 gene polymorphisms, associated with null or reduced enzyme activity, have been reported to negatively influence (in a gene-dose manner) the blood level of endoxifen in numerous prospective pharmacokinetic studies [11,172, 192-196], Some retrospective and prospective studies have shown that CYP2D6 polymorphism was associated with worse clinical outcomes in PMs and IMs patients in terms of recurrence and disease free survival or BC development in the chemo-prevention setting [192,194,195,197-205],... 

However, whether the monitoring of endoxifen plasma concentrations in breast cancer patients would constitute a valid approach to optimize individual dosage and improve treatment effectiveness remains to be demonstrated. So far, only one study... 

Whether the monitoring of endoxifen plasma concentrations in breast cancer patients would constitute a valid approach to optimize individual dosage and improve treatment efficacy is under scrutiny and remains to be demonstrated. In that purpose large prospective studies relating endoxifen plasma levels to clinical outcomes are as yet needed. In this perspective, it is critical to settle analytical and selectivity discrepancies between methods and laboratories and to ensure reproducible quantification results between laboratories. These concerted harmonization efforts can be carried out within the frame of an international external quality control program, which as yet, remains to be organized. 

Lim YC et al (2005) Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol 55 471 178... 

Lim YC et al (2006) Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J Pharmacol Exp Ther 318 503-512... 

Wu X et al (2009) The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res 69 1722-1727... 

Wu X et al (2011) Estrogen receptor-beta sensitizes breast cancer cells to the anti-estrogenic actions of endoxifen. Breast Cancer Res 13 R27... 

Teft WA et al (2011) Endoxifen, the active metabolite of tamoxifen, is a substrate of the efflux transporter P-glycoprotein (multidrug resistance 1). Drug Metab Dispos 39 558-562... 

IusufD et al (2011) P-glycoprotein (ABCB1) transports the primary active tamoxifen metabolites endoxifen and 4-hydroxytamoxifen and restricts their brain penetration. J Pharmacol ExpTher 337 710-717... 

Barginear MF et al (2011) Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels effect on active metabolite isomers and the antiestrogenic activity score. Clin Pharmacol Ther 90 605-611... 

Ahmad A et al (2010) Orally administered endoxifen is a new therapeutic agent for breast cancer. Breast Cancer Res Treat 122 579-584... 

Ahmad A et al (2010) Endoxifen, a new cornerstone of breast cancer therapy demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects. Clin Pharmacol Ther 88 814-817... 

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