Tissue distribution of 4-hydroxy-N-desmethyltamoxifen and tamoxifen-N-oxide

Gjerde, Jennifer; Gandini, Sara; Guerrieri-Gonzaga, Aliana; Haugan Moi, Line L.; Aristarco, Valentina; Mellgren, Gunnar; DeCensi, Andrea; Lien, Ernst A.

doi:10.1007/s10549-012-2074-9

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Tissue distribution of 4-hydroxy- N-desmethyltamoxifen and tamoxifen- N-oxide

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Author(s): Jennifer Gjerde ¹ ^, ² , Sara Gandini ³ , Aliana Guerrieri-Gonzaga ⁴ , Line L. Haugan Moi ⁵ , Valentina Aristarco ⁴ , Gunnar Mellgren ¹ ^, ² , Andrea DeCensi ⁴ ^, ⁶ , Ernst A. Lien ¹ ^, ² ^,

Publication date (Electronic): 5 May 2012

Journal: Breast Cancer Research and Treatment

Publisher: Springer US

Keywords: Breast cancer, Tamoxifen, 4-OH-N-desmethyltamoxifen, Endoxifen, Tamoxifen-N-oxide, MCF-7

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Abstract

Tamoxifen dosage is based on the one-dose-fits-all approach. The anticancer effect of tamoxifen is believed to be due to the metabolites, 4-hydroxytamoxifen (4OHtam), and 4-hydroxy- N-desmethyltamoxifen (4OHNDtam/endoxifen). These demethylated metabolites of tamoxifen have been associated with its side effects, whereas the effect mediated by tamoxifen- N-oxide (tamNox) is still poorly understood. Our objective was to improve the therapeutic index of tamoxifen by personalizing its dosage and maintaining serum tamoxifen metabolite concentrations within a target range. We examined the levels of tamoxifen, 4OHtam, 4OHNDtam, N-desmethyltamoxifen (NDtam), N-desdimethyltamoxifen (NDDtam), and tamNox in serum and in breast tumors specimens of 115 patients treated with 1, 5 or 20 mg/day of tamoxifen for 4 weeks before surgery in a randomized trial. Furthermore, the metabolism of tamNox in MCF-7 breast cancer cells was also studied. The concentrations of tamoxifen and its metabolites in tumor tissues were significantly correlated to their serum levels. Tumor tissue levels were 5–10 times higher than those measured in serum, with the exception of tamNox. In MCF-7 cells, tamNox was converted back to tamoxifen. In contrast to the tissue distribution of tamNox, the concentrations of 4OHtam and 4OHNDtam in tumor tissues corresponded to their serum levels. The results suggest that implementation of therapeutic drug monitoring may improve the therapeutic index of tamoxifen. Furthermore, the tissue distribution of tamNox deviated from that of the other tamoxifen metabolites.

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Most cited references 42

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Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis.

Eitan Amir, Saroj Niraula, Alberto Ocana … (2011)

Aromatase inhibitors are associated with consistent improvements in disease-free survival but not in overall survival. We conducted a literature-based meta-analysis of randomized trials to examine whether the relative toxicity of aromatase inhibitors compared with tamoxifen may explain this finding. We conducted a systematic review to identify randomized controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women by searching MEDLINE, EMBASE, and databases of the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm associated with one adverse event were computed for prespecified serious adverse events including cardiovascular disease, cerebrovascular disease, bone fractures, thromboembolic events, endometrial carcinoma and other second cancers not including new breast cancer. All statistical tests were two-sided. Seven trials enrolling 30,023 patients met the inclusion criteria. Longer duration of aromatase inhibitor use was associated with increased odds of developing cardiovascular disease (OR = 1.26, 95% CI = 1.10 to 1.43, P < .001; number needed to harm = 132) and bone fractures (OR = 1.47, 95% CI = 1.34 to 1.61, P < .001; number needed to harm = 46), but a decreased odds of venous thrombosis (OR = 0.55, 95% CI = 0.46 to 0.64, P < .001; number needed to harm = 79) and endometrial carcinoma (OR = 0.34, 95% CI = 0.22 to 0.53, P < .001; number needed to harm = 258). Five years of aromatase inhibitors was associated with a non-statistically significant increased odds of death without recurrence compared with 5 years of tamoxifen alone or tamoxifen for 2-3 years followed by an aromatase inhibitor for 2-3 years (OR = 1.11, 95% CI = 0.98 to 1.26, P = .09). The cumulative toxicity of aromatase inhibitors when used as up-front treatment may explain the lack of overall survival benefit despite improvements in disease-free survival. Switching from tamoxifen to aromatase inhibitors reduces this toxicity and is likely the best balance between efficacy and toxicity.

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Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine.

Vered Stearns, Michael D L Johnson, James Rae … (2003)

Tamoxifen, a selective estrogen receptor modulator (SERM), is converted to 4-hydroxy-tamoxifen and other active metabolites by cytochrome P450 (CYP) enzymes. Selective serotonin reuptake inhibitors (SSRIs), which are often prescribed to alleviate tamoxifen-associated hot flashes, can inhibit CYPs. In a prospective clinical trial, we tested the effects of coadministration of tamoxifen and the SSRI paroxetine, an inhibitor of CYP2D6, on tamoxifen metabolism. Tamoxifen and its metabolites were measured in the plasma of 12 women of known CYP2D6 genotype with breast cancer who were taking adjuvant tamoxifen before and after 4 weeks of coadministered paroxetine. We assessed the inhibitory activity of pure tamoxifen metabolites in an estradiol-stimulated MCF7 cell proliferation assay. To determine which CYP isoforms were involved in the metabolism of tamoxifen to specific metabolites, we used CYP isoform-specific inhibitors. All statistical tests were two-sided. We separated, purified, and identified the metabolite 4-hydroxy-N-desmethyl-tamoxifen, which we named endoxifen. Plasma concentrations of endoxifen statistically significantly decreased from a mean of 12.4 ng/mL before paroxetine coadministration to 5.5 ng/mL afterward (difference = 6.9 ng/mL, 95% confidence interval [CI] = 2.7 to 11.2 ng/mL) (P =.004). Endoxifen concentrations decreased by 64% (95% CI = 39% to 89%) in women with a wild-type CYP2D6 genotype but by only 24% (95% CI = 23% to 71%) in women with a variant CYP2D6 genotype (P =.03). Endoxifen and 4-hydroxy-tamoxifen inhibited estradiol-stimulated MCF7 cell proliferation with equal potency. In vitro, troleandomycin, an inhibitor of CYP3A4, inhibited the demethylation of tamoxifen to N-desmethyl-tamoxifen by 78% (95% CI = 65% to 91%), and quinidine, an inhibitor of CYP2D6, reduced the subsequent hydroxylation of N-desmethyl-tamoxifen to endoxifen by 79% (95% CI = 50% to 108%). Endoxifen is an active tamoxifen metabolite that is generated via CYP3A4-mediated N-demethylation and CYP2D6-mediated hydroxylation. Coadministration of paroxetine decreased the plasma concentration of endoxifen. Our data suggest that CYP2D6 genotype and drug interactions should be considered in women treated with tamoxifen.

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Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6.

Zeruesenay Desta, Bryan Ward, Nadia Soukhova … (2004)

We performed comprehensive kinetic, inhibition, and correlation analyses in human liver microsomes and experiments in expressed human cytochromes P450 (P450s) to identify primary and secondary metabolic routes of tamoxifen (TAM) and the P450s catalyzing these reactions at therapeutically relevant concentrations. N-Desmethyl-TAM formation catalyzed by CYP3A4/5 was quantitatively the major primary metabolite of TAM; 4-hydroxy-TAM formation catalyzed by CYP2D6 (and other P450s) represents a minor route. Other minor primary metabolites include alpha -, 3-, and 4'-hydroxyTAM and one unidentified metabolite (M-I) and were primarily catalyzed by CYP3A4, CYP3A5, CYP2B6/2C19, and CYP3A4, respectively. TAM secondary metabolism was examined using N-desmethyl- and 4-hydroxy-TAM as intermediate substrates. N-Desmethyl-TAM was predominantly biotransformed to alpha-hydroxy N-desmethyl-, N-didesmethyl-, and 4-hydroxy N-desmethyl-TAM (endoxifen), whereas 4-hydroxy-TAM was converted to 3,4-dihydroxyTAM and endoxifen. Except for the biotransformation of N-desmethyl-TAM to endoxifen, which was exclusively catalyzed by CYP2D6, all other routes of N-desmethyl- and 4-hydroxy-TAM biotransformation were catalyzed predominantly by the CYP3A subfamily. TAM and its primary metabolites undergo extensive oxidation, principally by CYP3A and CYP2D6 to metabolites that exhibit a range of pharmacological effects. Variable activity of these P450s, brought about by genetic polymorphisms and drug interactions, may alter the balance of TAM effects in vivo.

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Author and article information

Contributors

: 47-55974371 , 47-55975814 , Ernst.Lien@med.uib.no

Journal

Journal ID (nlm-ta): Breast Cancer Res Treat

Journal ID (iso-abbrev): Breast Cancer Res. Treat

Title: Breast Cancer Research and Treatment

Publisher: Springer US (Boston )

ISSN (Print): 0167-6806

ISSN (Electronic): 1573-7217

Publication date (Electronic): 5 May 2012

Publication date PMC-release: 5 May 2012

Publication date (Print): July 2012

Volume: 134

Issue: 2

Pages: 693-700

Affiliations

[1 ]Institute of Medicine, University of Bergen, Bergen, Norway

[2 ]Hormone Laboratory, Haukeland University Hospital, 5021 Bergen, Norway

[3 ]Division of Epidemiology and Biostatistic, European Institute of Oncology, Milan, Italy

[4 ]Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy

[5 ]Department of Clinical Pathology, The University Hospital of North Norway, Tromsø, Norway

[6 ]Division of Medical Oncology, Galliera Hospital, Genoa, Italy

Article

Publisher ID: 2074

DOI: 10.1007/s10549-012-2074-9

PMC ID: 3401496

PubMed ID: 22562123

SO-VID: 050e4d0f-73e4-4c72-8426-ac24e592bc4e

History

Date received : 12 March 2012

Date accepted : 17 April 2012

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tamoxifen-n-oxide,mcf-7,4-oh-n-desmethyltamoxifen,endoxifen,tamoxifen,breast cancer

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tamoxifen-n-oxide, mcf-7, 4-oh-n-desmethyltamoxifen, endoxifen, tamoxifen, breast cancer

Tissue distribution of 4-hydroxy- N-desmethyltamoxifen and tamoxifen- N-oxide

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Karger: Oncology

Most cited references 42

Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis.

Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine.

Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6.

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