Bitte benutzen Sie diese Referenz, um auf diese Ressource zu verweisen: doi:10.22028/D291-38307
Titel: Does the circulating ketoconazole metabolite N-deacetyl ketoconazole contribute to the drug-drug interaction potential of the parent compound?
VerfasserIn: Weiss, Johanna
Foerster, Kathrin Isabelle
Weber, Maria
Burhenne, Jürgen
Mikus, Gerd
Lehr, Thorsten
Haefeli, Walter Emil
Sprache: Englisch
Titel: European Journal of Pharmaceutical Sciences
Bandnummer: 169 (2022)
Verlag/Plattform: Elsevier
Erscheinungsjahr: 2021
Freie Schlagwörter: Ketoconazole
N-deacetyl ketoconazole
Drug-drug interaction
CYP
Drug transporters
UPLC-MS/MS
DDC-Sachgruppe: 500 Naturwissenschaften
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: Ketoconazole is a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and of P-glycoprotein (P-gp) and is often used as an index inhibitor especially for CYP3A4-mediated drug metabolism. A preliminary physiologically based pharmacokinetic (PBPK) model for drug-drug interactions indicated possible involvement of a metabolite to the perpetrator potential of ketoconazole. Still unknown for humans, in rodents, N-deacetyl ketoconazole (DAK) has been identified as the major ketoconazole metabolite. We therefore investigated in vitro, whether DAK also inhibits the human CYPs and drug transporters targeted by ketoconazole and quantified DAK in human plasma from healthy volunteers after receiving a single oral dose of 400 mg ketoconazole. Our data demonstrated that DAK also inhibits CYP3A4 (2.4-fold less potent than ketoconazole), CYP2D6 (13-fold more potent than ketoconazole), CYP2C19 (equally potent), P-gp (3.4-fold less potent than ketoconazole), breast cancer resistance protein (more potent than ketoconazole) and organic anion transporting polypeptide 1B1 and 1B3 (7.8-fold and 2.6-fold less potent than ketoconazole). After a single oral dose of 400 mg ketoconazole, maximum concentrations of DAK in human plasma were only 3.1 ‰ of the parent compound. However, assuming that DAK also highly accumulates in the human liver as demonstrated for rodents, inhibition of the proteins investigated could also be conceivable in vivo. In conclusion, DAK inhibits several CYPs and drug transporters, which might contribute to the perpetrator potential of ketoconazole.
DOI der Erstveröffentlichung: 10.1016/j.ejps.2021.106076
URL der Erstveröffentlichung: http://dx.doi.org/10.1016/j.ejps.2021.106076
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-383073
hdl:20.500.11880/34564
http://dx.doi.org/10.22028/D291-38307
ISSN: 0928-0987
Datum des Eintrags: 30-Nov-2022
Fakultät: NT - Naturwissenschaftlich- Technische Fakultät
Fachrichtung: NT - Pharmazie
Professur: NT - Prof. Dr. Thorsten Lehr
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

Dateien zu diesem Datensatz:
Datei Beschreibung GrößeFormat 
1-s2.0-S092809872100378X-main.pdf1,21 MBAdobe PDFÖffnen/Anzeigen


Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons Creative Commons