Ribociclib shows potential for pharmacokinetic drug-drug interactions being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450 isoforms in vitro
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
29673999
DOI
10.1016/j.bcp.2018.04.013
PII: S0006-2952(18)30156-4
Knihovny.cz E-zdroje
- Klíčová slova
- ABC transporters, CYP, Multidrug resistance, Pharmacokinetic interactions, Ribociclib,
- MeSH
- ABC transportér z rodiny G, člen 2 antagonisté a inhibitory metabolismus MeSH
- aminopyridiny farmakokinetika MeSH
- buňky MDCK MeSH
- inhibitory cytochromu P450 farmakokinetika MeSH
- izoenzymy antagonisté a inhibitory metabolismus MeSH
- lékové interakce fyziologie MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- nádorové proteiny antagonisté a inhibitory metabolismus MeSH
- P-glykoproteiny antagonisté a inhibitory metabolismus MeSH
- psi MeSH
- puriny farmakokinetika MeSH
- substrátová specifita účinky léků fyziologie MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- ABC transportér z rodiny G, člen 2 MeSH
- ABCB1 protein, human MeSH Prohlížeč
- ABCG2 protein, human MeSH Prohlížeč
- aminopyridiny MeSH
- inhibitory cytochromu P450 MeSH
- izoenzymy MeSH
- nádorové proteiny MeSH
- P-glykoproteiny MeSH
- puriny MeSH
- ribociclib MeSH Prohlížeč
- systém (enzymů) cytochromů P-450 MeSH
Ribociclib is a novel cyclin-dependent kinase (CDK) 4 and 6 selective inhibitor that recently gained breakthrough therapy status and global approval for advanced breast cancer treatment. ATP-binding cassette (ABC) transporters may become a site of severe drug interactions and a mechanism of multidrug resistance (MDR) development. With respect to rapid progress of ribociclib in the clinical field, we aimed to identify its interactions with ABC transporters and cytochrome P450 (CYP) isoenzymes and evaluate its potential to overcome transporter-mediated MDR using established in vitro methods. Our data showed accelerated ABCB1 inhibitor LY335979-sensitive, basolateral-to-apical transport of ribociclib across MDCKII-ABCB1 cell monolayers, which identified ribociclib as an ABCB1 substrate. The antiproliferative studies supported this finding by demonstrating significantly higher EC50 value in ABCB1-, but not ABCG2- or ABCC1-expressing MDCKII cells, than in the parent MDCKII cell line. Furthermore, we observed significant inhibitory effects of ribociclib on ABCB1 and ABCG2 transporters and CYP1A2, CYP3A4, CYP3A5, and CYP2C9 isoform activity in human CYP-expressing insect microsomes. The ribociclib-induced ABCB1 and ABCG2 inhibition further reversed daunorubicin and mitoxantrone resistance in MDCKII and human MCF-7 breast carcinoma cell lines, indicating a synergistic antiproliferative effect, without affecting ABCB1 or ABCG2 expression. In summary, our data indicate that ABCB1 affects ribociclib transport across the membranes and the high potential of ribociclib for drug-drug interactions (DDIs) through ABCB1 and ABCG2 transporters and CYP isoforms. Moreover, we demonstrate the beneficial MDR-reversing potential of ribociclib, which could be further exploited in novel anticancer treatment strategies.
Citace poskytuje Crossref.org
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