Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifenâ€treated Asian breast cancer patients The aim was to examine the influence of CYP2C19 variants and associated haplotypes on the disposition of tamoxifen and its metabolites, particularly norendoxifen (NorEND), in Asian patients with breast cancer. Sixty-six CYP2C19 polymorphisms were
Inhibition of Cytochrome P450 Enzymes by the E- and Z-Isomers of Norendoxifen Aromatase catalyzes the conversion of testosterone to estradiol and is the main source of endogenous estrogen in postmenopausal women. Aromatase inhibitors (AIs) are used to treat postmenopausal women with hormone receptor-positive breast cancer. Norendoxifen [4-(1-(4-(2-aminoethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenol ], an active metabolite of the selective estrogen receptor modulator tamoxifen, has been shown to be a potent competitive AI, with an IC50 of 90 nM. To obtain data relevant to the clinical use of norendoxifen, the primary objective of this study was to investigate norendoxifen's inhibitory capability on enzymes related to drug-drug interactions. We determined the inhibitory ability of norendoxifen against
. CYP2C19 2 predicts substantial tamoxifen benefit inpostmenopausal breast cancer patients randomized betweenadjuvant tamoxifen and no systemic treatment.Breast Cancer Res.Treat.139, 649–655 (2013).51. Lim, J.S.et al. Association of CYP2C19*2 and associated haplotypeswith lower norendoxifen concentrations in tamoxifen-treated Asianbreast cancer patients.Br. J. Clin. Pharmacol.81, 1142–1152(2016).52
showed highest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the activity of CYP2C enzymes while tamoxifen bisphenol consistently induced CYPs similar to rifampicin and phenobarbital. On the transcript level, highest induction up to 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4
degradation of tamoxifen and its metabolites. Otherwise, these substances could promote an undesired recombination, leading to data misinterpretation. We defined the optimal time window, allowing the complete degradation of tamoxifen and its metabolites, such as 4-hydroxytamoxifen, -desmethyltamoxifen, endoxifen and norendoxifen, in the mouse brain after intraperitoneal tamoxifen injection. We determined
A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β The design and synthesis of dual aromatase inhibitors/selective estrogen receptor modulators (AI/SERMs) is an attractive strategy for the discovery of new breast cancer therapeutic agents. Previous efforts led to the preparation of norendoxifen (4) derivatives with dual aromatase inhibitory activity and estrogen receptor binding activity. In the present study, some of the structural features of the potent AI letrozole were incorporated into the lead compound (norendoxifen) to afford a series of new dual AI/SERM agents based on a symmetrical diphenylmethylene substructure that eliminates the problem of E,Z isomerization encountered with norendoxifen-based AI/SERMs. Compound 12d had
recently been found that some of tamoxifen's metabolites (as norendoxifen) also act as aromatase inhibitors in vitro. Aromatase converts steroids (e.g., testosterone to estradiol), the inhibition of which severely decreases the amount of available estrogen in the body .The most common side effects of Tamoxifen: * Hot flashes, the most common side effect of tamoxifen, affect up to 80% of women : highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013 Sep;24(9):2206-23. doi: 10.1093/annonc/mdt303. Epub 2013 Aug 4. Lu WJ, Xu C, Pei Z, Mayhoub AS, Cushman M, Flockhart DA. The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents. Breast