Comprehensive in vitro analysis evaluating the variable drug-drug interaction risk of rifampicin compared to rifabutin.
ABCB1
CYP3A4
Induction
Pgp
Rifabutin
Rifampicin
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
27
04
2023
accepted:
24
05
2023
medline:
7
7
2023
pubmed:
7
6
2023
entrez:
7
6
2023
Statut:
ppublish
Résumé
Compared to rifampicin (600 mg/day), standard doses of rifabutin (300 mg/day) have a lower risk of drug-drug interactions due to induction of cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (Pgp/ABCB1) mediated by the pregnane X receptor (PXR). However, clinical comparisons with equal rifamycin doses or in vitro experiments respecting actual intracellular concentrations are lacking. Thus, the genuine pharmacological differences and the potential molecular mechanisms of the discordant perpetrator effects are unknown. Consequently, the cellular uptake kinetics (mass spectrometry), PXR activation (luciferase reporter gene assays), and impact on CYP3A4 and Pgp/ABCB1 expression and activity (polymerase chain reaction, enzymatic assays, flow cytometry) were evaluated in LS180 cells after treatment with different rifampicin or rifabutin concentrations for variable exposure times and eventually normalized to actual intracellular concentrations. In addition, inhibitory effects on CYP3A4 and Pgp activities were investigated. While rifampicin is poorly taken up by LS180 cells, it strongly activates PXR and leads to enhanced expression and activity of CYP3A4 and Pgp. In contrast, rifabutin is a significantly less potent and less efficient PXR activator and gene inducer, despite sixfold to eightfold higher intracellular accumulation. Finally, rifabutin is a potent inhibitor of Pgp (IC
Identifiants
pubmed: 37285043
doi: 10.1007/s00204-023-03531-2
pii: 10.1007/s00204-023-03531-2
pmc: PMC10322781
doi:
Substances chimiques
Rifampin
VJT6J7R4TR
Cytochrome P-450 CYP3A
EC 1.14.14.1
Rifabutin
1W306TDA6S
Receptors, Steroid
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2219-2230Informations de copyright
© 2023. The Author(s).
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