dc.contributor.author
Schulz, Josefine
dc.contributor.author
Thomas, Antonia
dc.contributor.author
Saleh, Ayatallah
dc.contributor.author
Mikus, Gerd
dc.contributor.author
Kloft, Charlotte
dc.contributor.author
Michelet, Robin
dc.date.accessioned
2022-03-31T12:31:42Z
dc.date.available
2022-03-31T12:31:42Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/34537
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-34255
dc.description.abstract
The small-molecule drug voriconazole (VRC) shows a complex and not yet fully understood metabolism. Consequently, its in vivo pharmacokinetics are challenging to predict, leading to therapy failures or adverse events. Thus, a quantitative in vitro characterization of the metabolism and inhibition properties of VRC for human CYP enzymes was aimed for. The Michaelis–Menten kinetics of voriconazole N-oxide (NO) formation, the major circulating metabolite, by CYP2C19, CYP2C9 and CYP3A4, was determined in incubations of human recombinant CYP enzymes and liver and intestine microsomes. The contribution of the individual enzymes to NO formation was 63.1% CYP2C19, 13.4% CYP2C9 and 29.5% CYP3A4 as determined by specific CYP inhibition in microsomes and intersystem extrapolation factors. The type of inhibition and inhibitory potential of VRC, NO and hydroxyvoriconazole (OH–VRC), emerging to be formed independently of CYP enzymes, were evaluated by their effects on CYP marker reactions. Time-independent inhibition by VRC, NO and OH–VRC was observed on all three enzymes with NO being the weakest and VRC and OH–VRC being comparably strong inhibitors of CYP2C9 and CYP3A4. CYP2C19 was significantly inhibited by VRC only. Overall, the quantitative in vitro evaluations of the metabolism contributed to the elucidation of the pharmacokinetics of VRC and provided a basis for physiologically-based pharmacokinetic modeling and thus VRC treatment optimization.
en
dc.format.extent
20 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
voriconazole
en
dc.subject
drug metabolism
en
dc.subject
pharmacokinetics
en
dc.subject
CYP P450 enzymes
en
dc.subject
CYP inhibition
en
dc.subject
intersystem extrapolation factors
en
dc.subject
time-dependent inhibition
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::615 Pharmakologie, Therapeutik
dc.title
Towards the Elucidation of the Pharmacokinetics of Voriconazole: A Quantitative Characterization of Its Metabolism
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
477
dcterms.bibliographicCitation.doi
10.3390/pharmaceutics14030477
dcterms.bibliographicCitation.journaltitle
Pharmaceutics
dcterms.bibliographicCitation.number
3
dcterms.bibliographicCitation.originalpublishername
MDPI
dcterms.bibliographicCitation.volume
14
dcterms.bibliographicCitation.url
https://doi.org/10.3390/pharmaceutics14030477
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Pharmazie

refubium.note.author
Die Publikation wurde aus Open Access Publikationsgeldern der Freien Universität Berlin gefördert.
de
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1999-4923