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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

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