Inhibition of cytochrome p450 enzymes by the e- and z-isomers of norendoxifen.

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Liu J, Flockhart PJ, Lu D, Lv W, Lu WJ, Han X, Cushman M, Flockhart DA

Inhibition of cytochrome p450 enzymes by the e- and z-isomers of norendoxifen.

Drug Metab Dispos. 2013 Sep;41(9):1715-20. doi: 10.1124/dmd.113.052506. Epub 2013 Jul 3.

PubMed ID

23824607 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Methoxyflurane	Cytochrome P450 2A6	Protein	Humans	Unknown	Substrate	Details

Drug Interactions

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• Vet approved
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• Illicit
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Drugs	Interaction
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Methadone Aminoglutethimide	The serum concentration of Methadone can be increased when it is combined with Aminoglutethimide.
Methadone Testolactone	The serum concentration of Methadone can be increased when it is combined with Testolactone.
Methadone Exemestane	The serum concentration of Methadone can be increased when it is combined with Exemestane.
Methadone Letrozole	The serum concentration of Methadone can be increased when it is combined with Letrozole.
Methadone Anastrozole	The serum concentration of Methadone can be increased when it is combined with Anastrozole.