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doi:10.22028/D291-38624
Titel: | Prediction of Drug–Drug–Gene Interaction Scenarios of (E)-Clomiphene and Its Metabolites Using Physiologically Based Pharmacokinetic Modeling |
VerfasserIn: | Kovar, Christina Kovar, Lukas Rüdesheim, Simeon Selzer, Dominik Ganchev, Boian Kröner, Patrick Igel, Svitlana Kerb, Reinhold Schaeffeler, Elke Mürdter, Thomas E. Schwab, Matthias Lehr, Thorsten |
Sprache: | Englisch |
Titel: | Pharmaceutics |
Bandnummer: | 14 |
Heft: | 12 |
Verlag/Plattform: | MDPI |
Erscheinungsjahr: | 2022 |
Freie Schlagwörter: | clomiphene pharmacokinetics cytochrome P450 2D6 (CYP2D6) polymorphisms drug–drug interactions (DDIs) drug–drug–gene interactions (DDGIs) drug–gene interactions (DGIs) (E)-clomiphene physiologically based pharmacokinetic (PBPK) modeling |
DDC-Sachgruppe: | 500 Naturwissenschaften |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | Clomiphene, a selective estrogen receptor modulator (SERM), has been used for the treatment of anovulation for more than 50 years. However, since (E)-clomiphene ((E)-Clom) and its metabolites are eliminated primarily via Cytochrome P450 (CYP) 2D6 and CYP3A4, exposure can be affected by CYP2D6 polymorphisms and concomitant use with CYP inhibitors. Thus, clomiphene therapy may be susceptible to drug–gene interactions (DGIs), drug–drug interactions (DDIs) and drug–drug–gene interactions (DDGIs). Physiologically based pharmacokinetic (PBPK) modeling is a tool to quantify such DGI and DD(G)I scenarios. This study aimed to develop a whole-body PBPK model of (E)-Clom including three important metabolites to describe and predict DGI and DD(G)I effects. Model performance was evaluated both graphically and by calculating quantitative measures. Here, 90% of predicted Cmax and 80% of AUClast values were within two-fold of the corresponding observed value for DGIs and DD(G)Is with clarithromycin and paroxetine. The model also revealed quantitative contributions of different CYP enzymes to the involved metabolic pathways of (E)-Clom and its metabolites. The developed PBPK model can be employed to assess the exposure of (E)-Clom and its active metabolites in as-yet unexplored DD(G)I scenarios in future studies. |
DOI der Erstveröffentlichung: | 10.3390/pharmaceutics14122604 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-386245 hdl:20.500.11880/34820 http://dx.doi.org/10.22028/D291-38624 |
ISSN: | 1999-4923 |
Datum des Eintrags: | 23-Dez-2022 |
Bezeichnung des in Beziehung stehenden Objekts: | Supplementary Materials |
In Beziehung stehendes Objekt: | https://www.mdpi.com/article/10.3390/pharmaceutics14122604/s1 |
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 | Größe | Format | |
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pharmaceutics-14-02604-v4.pdf | 2,03 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons