Dmd052506 1715..1720
نویسندگان
چکیده
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 Eand 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 6 9, 76 6 3, 375 6 6, 829 6 62, and 0.56 6 0.02 nM, respectively. E-Norendoxifen had a 9.3-fold-higher inhibitory ability than Z-norendoxifen against CYP19, while Eand 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
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Exhaled breath condensate is not suitable to detect EGFR somatic mutations.
REFERENCES 1 Rosias PP, Jobsis Q, van de Kant K, et al. Global condensation: a ‘‘climate change’’ towards better standardisation of exhaled breath condensate measurements. Eur Respir J 2008; 31: 684–685. 2 Liu J, Conrad DH, Chow S, Tran VH, Yates DH, Thomas PS. Collection devices influence the constituents of exhaled breath condensate. Eur Respir J 2007; 30: 807–808. 3 Prieto L, Ferrer A, Palop...
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