Ribociclib shows potential for pharmacokinetic drug-drug interactions being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450 isoforms in vitro
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
29673999
DOI
10.1016/j.bcp.2018.04.013
PII: S0006-2952(18)30156-4
Knihovny.cz E-resources
- Keywords
- ABC transporters, CYP, Multidrug resistance, Pharmacokinetic interactions, Ribociclib,
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 antagonists & inhibitors metabolism MeSH
- Aminopyridines pharmacokinetics MeSH
- Madin Darby Canine Kidney Cells MeSH
- Cytochrome P-450 Enzyme Inhibitors pharmacokinetics MeSH
- Isoenzymes antagonists & inhibitors metabolism MeSH
- Drug Interactions physiology MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Neoplasm Proteins antagonists & inhibitors metabolism MeSH
- ATP Binding Cassette Transporter, Subfamily B antagonists & inhibitors metabolism MeSH
- Dogs MeSH
- Purines pharmacokinetics MeSH
- Substrate Specificity drug effects physiology MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Dogs MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
- ABCB1 protein, human MeSH Browser
- ABCG2 protein, human MeSH Browser
- Aminopyridines MeSH
- Cytochrome P-450 Enzyme Inhibitors MeSH
- Isoenzymes MeSH
- Neoplasm Proteins MeSH
- ATP Binding Cassette Transporter, Subfamily B MeSH
- Purines MeSH
- ribociclib MeSH Browser
- Cytochrome P-450 Enzyme System 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.
References provided by Crossref.org
Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors
