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doi:10.22028/D291-33452
Titel: | Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug–Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach |
VerfasserIn: | Fuhr, Laura Maria Marok, Fatima Zahra Hanke, Nina Selzer, Dominik Lehr, Thorsten |
Sprache: | Englisch |
Titel: | Pharmaceutics |
Bandnummer: | 13 |
Heft: | 2 |
Verlag/Plattform: | MDPI |
Erscheinungsjahr: | 2021 |
Freie Schlagwörter: | physiologically based pharmacokinetic (PBPK) modeling carbamazepine carbamazepine10,11-epoxide drug–drug interactions (DDIs) cytochrome P450 3A4 (CYP3A4) cytochrome P450 2B6 (CYP2B6) induction |
DDC-Sachgruppe: | 500 Naturwissenschaften |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | The anticonvulsant carbamazepine is frequently used in the long-term therapy of epilepsy and is a known substrate and inducer of cytochrome P450 (CYP) 3A4 and CYP2B6. Carbamazepine induces the metabolism of various drugs (including its own); on the other hand, its metabolism can be affected by various CYP inhibitors and inducers. The aim of this work was to develop a physiologically based pharmacokinetic (PBPK) parent−metabolite model of carbamazepine and its metabolite carbamazepine-10,11-epoxide, including carbamazepine autoinduction, to be applied for drug–drug interaction (DDI) prediction. The model was developed in PK-Sim, using a total of 92 plasma concentration−time profiles (dosing range 50–800 mg), as well as fractions excreted unchanged in urine measurements. The carbamazepine model applies metabolism by CYP3A4 and CYP2C8 to produce carbamazepine-10,11-epoxide, metabolism by CYP2B6 and UDP-glucuronosyltransferase (UGT) 2B7 and glomerular filtration. The carbamazepine-10,11-epoxide model applies metabolism by epoxide hydroxylase 1 (EPHX1) and glomerular filtration. Good DDI performance was demonstrated by the prediction of carbamazepine DDIs with alprazolam, bupropion, erythromycin, efavirenz and simvastatin, where 14/15 DDI AUClast ratios and 11/15 DDI Cmax ratios were within the prediction success limits proposed by Guest et al. The thoroughly evaluated model will be freely available in the Open Systems Pharmacology model repository. |
DOI der Erstveröffentlichung: | 10.3390/pharmaceutics13020270 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-334520 hdl:20.500.11880/30759 http://dx.doi.org/10.22028/D291-33452 |
ISSN: | 1999-4923 |
Datum des Eintrags: | 1-Mär-2021 |
Bezeichnung des in Beziehung stehenden Objekts: | Supplementary Materials |
In Beziehung stehendes Objekt: | https://www.mdpi.com/1999-4923/13/2/270/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-13-00270-v2.pdf | 4,39 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons