Alisertib shows negligible potential for perpetrating pharmacokinetic drug-drug interactions on ABCB1, ABCG2 and cytochromes P450, but acts as dual-activity resistance modulator through the inhibition of ABCC1 transporter
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
34896433
DOI
10.1016/j.taap.2021.115823
PII: S0041-008X(21)00427-0
Knihovny.cz E-resources
- Keywords
- ABC transporter, Alisertib, Cancer, Cytochrome P450, Multidrug resistance, Pharmacokinetic drug-drug interaction,
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics metabolism MeSH
- Azepines pharmacokinetics pharmacology MeSH
- Cell Line MeSH
- Catalytic Domain MeSH
- Protein Conformation MeSH
- Drug Interactions MeSH
- Humans MeSH
- Models, Molecular MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics metabolism MeSH
- Multidrug Resistance-Associated Proteins antagonists & inhibitors MeSH
- Dogs MeSH
- Pyrimidines pharmacokinetics pharmacology MeSH
- Gene Expression Regulation drug effects MeSH
- Molecular Docking Simulation 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
- Azepines MeSH
- MLN 8237 MeSH Browser
- multidrug resistance-associated protein 1 MeSH Browser
- ATP Binding Cassette Transporter, Subfamily B, Member 1 MeSH
- Multidrug Resistance-Associated Proteins MeSH
- Pyrimidines MeSH
- Cytochrome P-450 Enzyme System MeSH
Alisertib (MLN8237), a novel Aurora A kinase inhibitor, is currently being clinically tested in late-phase trials for the therapy of various malignancies. In the present work, we describe alisertib's potential to perpetrate pharmacokinetic drug-drug interactions (DDIs) and/or to act as an antagonist of multidrug resistance (MDR). In accumulation assays, alisertib potently inhibited ABCC1 transporter, but not ABCB1 or ABCG2. The results of molecular modeling suggested a bifunctional mechanism for interaction on ABCC1. In addition, alisertib was characterized as a low- to moderate-affinity inhibitor of recombinant CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 isoenzymes, but without potential clinical relevance. Drug combination studies revealed the capability of alisertib to synergistically antagonize ABCC1-mediated resistance to daunorubicin. Although alisertib exhibited substrate characteristics toward ABCB1 transporter in monolayer transport assays, comparative proliferation studies showed lack of its MDR-victim behavior in cells overexpressing ABCB1 as well as ABCG2 and ABCC1. Lastly, alisertib did not affect the expression of ABCC1, ABCG2, ABCB1 transporters and CYP1A2, CYP3A4, CYP2B6 isozymes on mRNA level in various systemic and tumoral models. In conclusion, our study suggests that alisertib is a drug candidate with negligible potential for perpetrating systemic pharmacokinetic DDIs on ABCB1, ABCG2 and cytochromes P450. In addition, we introduce alisertib as an effective dual-activity chemosensitizer whose MDR-antagonistic capacities are not impaired by efflux or effect on MDR phenotype. Our in vitro findings provide important pieces of information for clinicians when introducing alisertib into the clinical area.
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