<p>Tamoxifen can by hydroxylated to α-hydroxytamoxifen which is then glucuronidated or undergoes sulfate conjugation by sulfotransferase 2A1.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Squirewell EJ, Qin X, Duffel MW: Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50. doi: 10.1124/dmd.114.059709. Epub 2014 Aug 25. (PubMed ID 25157097)" href="#reference-A182102">4</a>,<a class="reference-popover-link" data-content="White IN: The tamoxifen dilemma. Carcinogenesis. 1999 Jul;20(7):1153-60. doi: 10.1093/carcin/20.7.1153. (PubMed ID 10383884)" href="#reference-A182108">6</a></sup> Tamoxifen can also undergo N-oxidation by flavin monooxygenases 1 and 3 to tamoxifen N-oxide.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Squirewell EJ, Qin X, Duffel MW: Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50. doi: 10.1124/dmd.114.059709. Epub 2014 Aug 25. (PubMed ID 25157097)" href="#reference-A182102">4</a>,<a class="reference-popover-link" data-content="White IN: The tamoxifen dilemma. Carcinogenesis. 1999 Jul;20(7):1153-60. doi: 10.1093/carcin/20.7.1153. (PubMed ID 10383884)" href="#reference-A182108">6</a>,<a class="reference-popover-link" data-content="Parte P, Kupfer D: Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. Drug Metab Dispos. 2005 Oct;33(10):1446-52. doi: 10.1124/dmd.104.000802. Epub 2005 Jun 29. (PubMed ID 15987777)" href="#reference-A182111">7</a></sup> Tamoxifen is N-dealkylated to N-desmethyltamoxifen by CYP2D6, CYP1A1, CYP1A2, CYP3A4, CYP1B1, CYP2C9, CYP2C19, and CYP3A5.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam EM: Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002 Aug;30(8):869-74. (PubMed ID 12124303)" href="#reference-A14873">3</a>,<a class="reference-popover-link" data-content="Squirewell EJ, Qin X, Duffel MW: Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50. doi: 10.1124/dmd.114.059709. Epub 2014 Aug 25. (PubMed ID 25157097)" href="#reference-A182102">4</a>,<a class="reference-popover-link" data-content="Cronin-Fenton DP, Damkier P, Lash TL: Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncol. 2014 Jan;10(1):107-22. doi: 10.2217/fon.13.168. (PubMed ID 24328412)" href="#reference-A182105">5</a>,<a class="reference-popover-link" data-content="White IN: The tamoxifen dilemma. Carcinogenesis. 1999 Jul;20(7):1153-60. doi: 10.1093/carcin/20.7.1153. (PubMed ID 10383884)" href="#reference-A182108">6</a>,<a class="reference-popover-link" data-content="Parte P, Kupfer D: Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. Drug Metab Dispos. 2005 Oct;33(10):1446-52. doi: 10.1124/dmd.104.000802. Epub 2005 Jun 29. (PubMed ID 15987777)" href="#reference-A182111">7</a></sup> N-desmethyltamoxifen can be sulfate conjugated to form N-desmethyltamoxifen sulfate, 4-hydroxylated by CYP2D6 to form endoxifen, or N-dealkylated again by CYP3A4 and CYP3A5 to N,N-didesmethyltamoxifen.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Squirewell EJ, Qin X, Duffel MW: Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50. doi: 10.1124/dmd.114.059709. Epub 2014 Aug 25. (PubMed ID 25157097)" href="#reference-A182102">4</a>,<a class="reference-popover-link" data-content="Cronin-Fenton DP, Damkier P, Lash TL: Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncol. 2014 Jan;10(1):107-22. doi: 10.2217/fon.13.168. (PubMed ID 24328412)" href="#reference-A182105">5</a>,<a class="reference-popover-link" data-content="Klein DJ, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE: PharmGKB summary: tamoxifen pathway, pharmacokinetics. Pharmacogenet Genomics. 2013 Nov;23(11):643-7. doi: 10.1097/FPC.0b013e3283656bc1. (PubMed ID 23962908)" href="#reference-A182183">13</a></sup> N,N-didesmethyltamoxifen undergoes a substitution reaction to form tamoxifen metabolite Y, followed by ether cleavage to metabolite E, which can then be sulfate conjugated by sulfotransferase 1A1 and 1E1 or O-glucuronidated.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Klein DJ, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE: PharmGKB summary: tamoxifen pathway, pharmacokinetics. Pharmacogenet Genomics. 2013 Nov;23(11):643-7. doi: 10.1097/FPC.0b013e3283656bc1. (PubMed ID 23962908)" href="#reference-A182183">13</a>,<a class="reference-popover-link" data-content="Kemp JV, Adam HK, Wakeling AE, Slater R: Identification and biological activity of tamoxifen metabolites in human serum. Biochem Pharmacol. 1983 Jul 1;32(13):2045-52. doi: 10.1016/0006-2952(83)90425-2. (PubMed ID 6870933)" href="#reference-A182249">14</a></sup></p><p>Tamoxifen can also by 4-hydroxylated by CYP2D6, CYP2B6, CYP3A4, CYP2C9, and CYP2C19 to form 4-hydroxytamoxifen.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam EM: Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002 Aug;30(8):869-74. (PubMed ID 12124303)" href="#reference-A14873">3</a>,<a class="reference-popover-link" data-content="Squirewell EJ, Qin X, Duffel MW: Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50. doi: 10.1124/dmd.114.059709. Epub 2014 Aug 25. (PubMed ID 25157097)" href="#reference-A182102">4</a>,<a class="reference-popover-link" data-content="Cronin-Fenton DP, Damkier P, Lash TL: Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncol. 2014 Jan;10(1):107-22. doi: 10.2217/fon.13.168. (PubMed ID 24328412)" href="#reference-A182105">5</a>,<a class="reference-popover-link" data-content="White IN: The tamoxifen dilemma. Carcinogenesis. 1999 Jul;20(7):1153-60. doi: 10.1093/carcin/20.7.1153. (PubMed ID 10383884)" href="#reference-A182108">6</a></sup> 4-hydroxytamoxifen can undergo glucuronidation by UGT1A8, UGT1A10, UGT2B7, and UGT2B17 to tamoxifen glucuronides, sulfate conjugation by sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, or N-dealkylation by CYP3A4 and CYP3A5 to endoxifen.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Squirewell EJ, Qin X, Duffel MW: Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50. doi: 10.1124/dmd.114.059709. Epub 2014 Aug 25. (PubMed ID 25157097)" href="#reference-A182102">4</a>,<a class="reference-popover-link" data-content="Cronin-Fenton DP, Damkier P, Lash TL: Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncol. 2014 Jan;10(1):107-22. doi: 10.2217/fon.13.168. (PubMed ID 24328412)" href="#reference-A182105">5</a></sup></p><p>Endoxifen undergoes demethylation to norendoxifen, a reversible sulfate conjugation reaction via sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, sulfate conjugation via sulfotransferase 2A1 to 4-endoxifen sulfate, or glucuronidation via UGT1A8, UGT1A10, UGT2B7, or UGT2B15 to tamoxifen glucuronides.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Klein DJ, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE: PharmGKB summary: tamoxifen pathway, pharmacokinetics. Pharmacogenet Genomics. 2013 Nov;23(11):643-7. doi: 10.1097/FPC.0b013e3283656bc1. (PubMed ID 23962908)" href="#reference-A182183">13</a>,<a class="reference-popover-link" data-content="Squirewell EJ, Qin X, Duffel MW: Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50. doi: 10.1124/dmd.114.059709. Epub 2014 Aug 25. (PubMed ID 25157097)" href="#reference-A182102">4</a>,<a class="reference-popover-link" data-content="Cronin-Fenton DP, Damkier P, Lash TL: Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncol. 2014 Jan;10(1):107-22. doi: 10.2217/fon.13.168. (PubMed ID 24328412)" href="#reference-A182105">5</a></sup></p><p class="d-none d-sm-block"><strong>Hover over products below to view reaction partners</strong></p>