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

Toxicol Appl Pharmacol. 2022 Jan 1:434:115823. doi: 10.1016/j.taap.2021.115823. Epub 2021 Dec 9.

Abstract

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.

Keywords: ABC transporter; Alisertib; Cancer; Cytochrome P450; Multidrug resistance; Pharmacokinetic drug-drug interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism*
  • Animals
  • Azepines / pharmacokinetics*
  • Azepines / pharmacology*
  • Catalytic Domain
  • Cell Line
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Gene Expression Regulation / drug effects
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
  • Protein Conformation
  • Pyrimidines / pharmacokinetics*
  • Pyrimidines / pharmacology*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Azepines
  • MLN 8237
  • Multidrug Resistance-Associated Proteins
  • Pyrimidines
  • Cytochrome P-450 Enzyme System
  • multidrug resistance-associated protein 1