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Status: Bibliographieeintrag

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Verfasst von:Phondeth, Lottida [VerfasserIn]   i
 Kamaraj, Rajamanikkam [VerfasserIn]   i
 Nilles, Julie [VerfasserIn]   i
 Weiß, Johanna [VerfasserIn]   i
 Haefeli, Walter E. [VerfasserIn]   i
 Pávek, Petr [VerfasserIn]   i
 Theile, Dirk [VerfasserIn]   i
Titel:Rifabutin but not rifampicin can partly out-balance P-glycoprotein induction by concurrent P-glycoprotein inhibition through high affinity binding to the inhibitory site
Verf.angabe:Lottida Phondeth, Rajamanikkam Kamaraj, Julie Nilles, Johanna Weiss, Walter E. Haefeli, Petr Pávek, Dirk Theile
E-Jahr:2023
Jahr:14 October 2023
Umfang:9 S.
Illustrationen:Illustrationen
Fussnoten:Online veröffentlicht: 14. Oktober 2023 ; Gesehen am 20.12.2023
Titel Quelle:Enthalten in: Archives of toxicology
Ort Quelle:Berlin : Springer, 1930
Jahr Quelle:2023
Band/Heft Quelle:(2023), online ahead of print
ISSN Quelle:1432-0738
Abstract:Physiology-based pharmacokinetic modeling suggests that rifabutin can out-balance P-glycoprotein (P-gp) induction by concurrent P-gp inhibition. However, clinical or experimental evidence for this Janus-faced rifabutin effect is missing. Consequently, LS180 cells were exposed to a moderately (2 µM) and strongly (10 µM) P-gp-inducing concentration of rifampicin or rifabutin for 6 days. Cellular accumulation of the fluorescent P-gp substrate rhodamine 123 was evaluated using flow cytometry, either without (induction only) or with adding rifamycin drug to the cells during the rhodamine 123 efflux phase (induction + potential inhibition). Rhodamine 123 accumulation was decreased similarly by both drugs after 6-day exposure (2 µM: 55% residual fluorescence compared to non-induced cells, P < 0.01; 10 µM: 30% residual fluorescence compared to non-induced cells, P < 0.001), indicating P-gp induction. Rhodamine 123 influx transporters mRNA expressions were not affected, excluding off-target effects. Acute re-exposure to rifabutin, however, considerably re-increased rhodamine 123 accumulation (2 µM induction: re-increase by 55%, P < 0.01; 10 µM induction: 49% re-increase, P < 0.001), suggesting P-gp inhibition. In contrast, rifampicin only had weak effects (2 µM induction: no re-increase; 10 µM induction: 16% re-increase; P < 0.05). Molecular docking analysis eventually revealed that rifabutin has a higher binding affinity to the inhibitor binding site of P-gp than rifampicin (ΔG (kcal/mol) = −11.5 vs −5.3). Together, this study demonstrates that rifabutin can at least partly mask P-gp induction by P-gp inhibition, mediated by high affinity binding to the inhibitory site of P-gp.
DOI:doi:10.1007/s00204-023-03618-w
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

kostenfrei: Volltext: https://doi.org/10.1007/s00204-023-03618-w
 DOI: https://doi.org/10.1007/s00204-023-03618-w
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:Induction
 Inhibition
 P-glycoprotein
 Rifabutin
 Rifampicin
K10plus-PPN:1876538376
Verknüpfungen:→ Zeitschrift

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