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Verfasst von:Weiß, Johanna [VerfasserIn]   i
 Kocher, Jutta [VerfasserIn]   i
 Mueller, Corina [VerfasserIn]   i
 Rosenzweig, Stephanie [VerfasserIn]   i
 Theile, Dirk [VerfasserIn]   i
Titel:Impact of enzalutamide and its main metabolite N-desmethyl enzalutamide on pharmacokinetically important drug metabolizing enzymes and drug transporters
Verf.angabe:Johanna Weiss, Jutta Kocher, Corina Mueller, Stephanie Rosenzweig, Dirk Theile
E-Jahr:2017
Jahr:December 2017
Umfang:9 S.
Fussnoten:Gesehen am 22.11.2018
Titel Quelle:Enthalten in: Biopharmaceutics & drug disposition
Ort Quelle:New York, NY [u.a.] : Wiley, 1980
Jahr Quelle:2017
Band/Heft Quelle:38(2017), 9, Seite 517-525
ISSN Quelle:1099-081X
Abstract:Enzalutamide is a new drug against castration-resistant prostate cancer. Recent data indicate profound induction of drug metabolizing enzymes (e.g. cytochrome P450 isoenzyme (CYP) 3A4) but comprehensive in vitro data on other CYP enzymes, drug conjugating enzymes or drug transporters is scarce. Moreover, the mechanisms of induction are poorly investigated and the effects of the active metabolite N-desmethyl enzalutamide are unknown. Using LS180 cells as an induction model and quantitative real-time reverse transcription polymerase chain reaction, our study demonstrated a concentration-dependent induction of CYP1A1, CYP1A2, CYP3A5, CYP3A4, UGT1A3, UGT1A9, ABCB1, ABCC2 and ABCG2 mRNA. Induction of CYP3A4 and ABCB1 was confirmed by Western blot analysis and is likely mediated by activation of the nuclear receptor pregnane x receptor, elucidated by a luciferase-based reporter gene assay. Enzalutamide's main active metabolite N-desmethyl enzalutamide exhibited only weak induction properties. mRNA expression of UGT2B7 was suppressed by enzalutamide and its metabolite. Both compounds are apparently not transported by P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). N-desmethyl enzalutamide more potently inhibited important drug transporters (P-gp, BCRP, OATPs) than enzalutamide. Taken together, the pharmacokinetics of concurrently administered drugs is likely altered during enzalutamide therapy. Levels of metabolically (mainly CYP3A4) eliminated drugs are expected to be decreased, whereas the abundance of compounds with solely transporter-determined pharmacokinetics (P-gp, OATPs) is likely enhanced.
DOI:doi:10.1002/bdd.2103
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext ; Verlag: http://dx.doi.org/10.1002/bdd.2103
 Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/bdd.2103
 DOI: https://doi.org/10.1002/bdd.2103
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:drug interactions
 drug metabolizing enzymes
 drug transporters
 enzalutamide
 N-desmethyl enzalutamide
K10plus-PPN:1583952594
Verknüpfungen:→ Zeitschrift

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