| Online-Ressource |
Verfasst von: | Phondeth, Lottida [VerfasserIn]  |
| Kamaraj, Rajamanikkam [VerfasserIn]  |
| Nilles, Julie [VerfasserIn]  |
| Weiß, Johanna [VerfasserIn]  |
| Haefeli, Walter E. [VerfasserIn]  |
| Pávek, Petr [VerfasserIn]  |
| Theile, Dirk [VerfasserIn]  |
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 |
Rifabutin but not rifampicin can partly out-balance P-glycoprotein induction by concurrent P-glycoprotein inhibition through high affinity binding to the inhibitory site / Phondeth, Lottida [VerfasserIn]; 14 October 2023 (Online-Ressource)