dc.contributor.author
Lehmann, Anja
dc.contributor.author
Geburek, Ina
dc.contributor.author
Hessel-Pras, Stefanie
dc.contributor.author
Enge, Anne-Margarethe
dc.contributor.author
Mielke, Hans
dc.contributor.author
Müller-Graf, Christine
dc.contributor.author
Kloft, Charlotte
dc.contributor.author
Hethey, Christoph
dc.date.accessioned
2024-05-30T08:32:49Z
dc.date.available
2024-05-30T08:32:49Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/43550
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-43266
dc.description.abstract
Cytochrome P450 (CYP)3A4 induction by drugs and pesticides plays a critical role in the enhancement of pyrrolizidine alkaloid (PA) toxicity as it leads to increased formation of hepatotoxic dehydro-PA metabolites. Addressing the need for a quantitative analysis of this interaction, we developed a physiologically-based toxicokinetic (PBTK) model. Specifically, the model describes the impact of the well-characterized CYP3A4 inducer rifampicin on the kinetics of retrorsine, which is a prototypic PA and contaminant in herbal teas. Based on consumption data, the kinetics after daily intake of retrorsine were simulated with concomitant rifampicin treatment. Strongest impact on retrorsine kinetics (plasma AUC24 and Cmax reduced to 67% and 74% compared to the rifampicin-free reference) was predicted directly after withdrawal of rifampicin. At this time point, the competitive inhibitory effect of rifampicin stopped, while CYP3A4 induction was still near its maximum. Due to the impacted metabolism kinetics, the cumulative formation of intestinal retrorsine CYP3A4 metabolites increased to 254% (from 10 to 25 nmol), while the cumulative formation of hepatic CYP3A4 metabolites was not affected (57 nmol). Return to baseline PA toxicokinetics was predicted 14 days after stop of a 14-day rifampicin treatment. In conclusion, the PBTK model showed to be a promising tool to assess the dynamic interplay of enzyme induction and toxification pathways.
en
dc.format.extent
13 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
Drug–drug interaction
en
dc.subject
Enzyme induction
en
dc.subject
Bioactivation
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::615 Pharmakologie, Therapeutik
dc.title
PBTK model-based analysis of CYP3A4 induction and the toxicokinetics of the pyrrolizidine alkaloid retrorsine in man
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1007/s00204-024-03698-2
dcterms.bibliographicCitation.journaltitle
Archives of Toxicology
dcterms.bibliographicCitation.number
6
dcterms.bibliographicCitation.pagestart
1757
dcterms.bibliographicCitation.pageend
1769
dcterms.bibliographicCitation.volume
98
dcterms.bibliographicCitation.url
https://doi.org/10.1007/s00204-024-03698-2
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Pharmazie
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refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1432-0738
refubium.resourceType.provider
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