Inhibition of cytochrome P450 enzymes by the E-and Z-isomers of norendoxifen

Jinzhong Liu, Peter J. Flockhart, Deshun Lu, Wei Lv, Wenjie Jessie Lu, Xu Han, Mark Cushman, David A. Flockhart

Research output: Contribution to journalArticle

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Abstract

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 important drug-metabolizing cytochrome P450 enzymes, including CYP1A2, CYP2A6, CYP3A4, CYP3A5, and CYP2C19, to establish the potency of norendoxifen as a potential cause of drug-drug interactions. A second objective was to determine the effects of E- and Z-norendoxifen on the inhibition of these enzymes to further characterize the isomers' selectivity. The inhibitory abilities of E-, mixed, and Z-norendoxifen against recombinant aromatase (CYP19), CYP1A2, CYP3A4, CYP3A5, and CYP2C19 were tested using microsomal incubations. Mixed norendoxifen inhibited these enzymes with Ki values of 70 ± 9, 76 ± 3, 375 ± 6, 829 ± 62, and 0.56 ± 0.02 nM, respectively. E-Norendoxifen had a 9.3-fold-higher inhibitory ability than Z-norendoxifen against CYP19, while E- and Z-norendoxifen had similar potencies against CYP1A2, CYP3A4, CYP3A5, and CYP2C19. These results suggest that norendoxifen is able to act as a potent AI, and that its E-isomer is 9.3-fold more potent than the Z-isomer.

Original languageEnglish
Pages (from-to)1715-1720
Number of pages6
JournalDrug Metabolism and Disposition
Volume41
Issue number9
DOIs
StatePublished - Sep 2013

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Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP3A
Aromatase
Cytochrome P-450 CYP1A2
Aromatase Inhibitors
Drug Interactions
N,N-didesmethyl-4-hydroxytamoxifen
Enzymes
Pharmaceutical Preparations
Selective Estrogen Receptor Modulators
Tamoxifen
Phenol
Inhibitory Concentration 50
Testosterone
Estradiol
Estrogens
Hormones
Breast Neoplasms

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Liu, J., Flockhart, P. J., Lu, D., Lv, W., Lu, W. J., Han, X., ... Flockhart, D. A. (2013). Inhibition of cytochrome P450 enzymes by the E-and Z-isomers of norendoxifen. Drug Metabolism and Disposition, 41(9), 1715-1720. https://doi.org/10.1124/dmd.113.052506

Inhibition of cytochrome P450 enzymes by the E-and Z-isomers of norendoxifen. / Liu, Jinzhong; Flockhart, Peter J.; Lu, Deshun; Lv, Wei; Lu, Wenjie Jessie; Han, Xu; Cushman, Mark; Flockhart, David A.

In: Drug Metabolism and Disposition, Vol. 41, No. 9, 09.2013, p. 1715-1720.

Research output: Contribution to journalArticle

Liu, J, Flockhart, PJ, Lu, D, Lv, W, Lu, WJ, Han, X, Cushman, M & Flockhart, DA 2013, 'Inhibition of cytochrome P450 enzymes by the E-and Z-isomers of norendoxifen', Drug Metabolism and Disposition, vol. 41, no. 9, pp. 1715-1720. https://doi.org/10.1124/dmd.113.052506
Liu, Jinzhong ; Flockhart, Peter J. ; Lu, Deshun ; Lv, Wei ; Lu, Wenjie Jessie ; Han, Xu ; Cushman, Mark ; Flockhart, David A. / Inhibition of cytochrome P450 enzymes by the E-and Z-isomers of norendoxifen. In: Drug Metabolism and Disposition. 2013 ; Vol. 41, No. 9. pp. 1715-1720.
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abstract = "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 important drug-metabolizing cytochrome P450 enzymes, including CYP1A2, CYP2A6, CYP3A4, CYP3A5, and CYP2C19, to establish the potency of norendoxifen as a potential cause of drug-drug interactions. A second objective was to determine the effects of E- and Z-norendoxifen on the inhibition of these enzymes to further characterize the isomers' selectivity. The inhibitory abilities of E-, mixed, and Z-norendoxifen against recombinant aromatase (CYP19), CYP1A2, CYP3A4, CYP3A5, and CYP2C19 were tested using microsomal incubations. Mixed norendoxifen inhibited these enzymes with Ki values of 70 ± 9, 76 ± 3, 375 ± 6, 829 ± 62, and 0.56 ± 0.02 nM, respectively. E-Norendoxifen had a 9.3-fold-higher inhibitory ability than Z-norendoxifen against CYP19, while E- and Z-norendoxifen had similar potencies against CYP1A2, CYP3A4, CYP3A5, and CYP2C19. These results suggest that norendoxifen is able to act as a potent AI, and that its E-isomer is 9.3-fold more potent than the Z-isomer.",
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AB - 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 important drug-metabolizing cytochrome P450 enzymes, including CYP1A2, CYP2A6, CYP3A4, CYP3A5, and CYP2C19, to establish the potency of norendoxifen as a potential cause of drug-drug interactions. A second objective was to determine the effects of E- and Z-norendoxifen on the inhibition of these enzymes to further characterize the isomers' selectivity. The inhibitory abilities of E-, mixed, and Z-norendoxifen against recombinant aromatase (CYP19), CYP1A2, CYP3A4, CYP3A5, and CYP2C19 were tested using microsomal incubations. Mixed norendoxifen inhibited these enzymes with Ki values of 70 ± 9, 76 ± 3, 375 ± 6, 829 ± 62, and 0.56 ± 0.02 nM, respectively. E-Norendoxifen had a 9.3-fold-higher inhibitory ability than Z-norendoxifen against CYP19, while E- and Z-norendoxifen had similar potencies against CYP1A2, CYP3A4, CYP3A5, and CYP2C19. These results suggest that norendoxifen is able to act as a potent AI, and that its E-isomer is 9.3-fold more potent than the Z-isomer.

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