Can P-glycoprotein influence the bioavailability of iminosugar-based glucosylceramide synthase inhibitors?

Edward Norris-Cervetto, Terry D. Butters, Catherine Martin, Szabolcs Modok, Raymond A. Dwek, Richard Callaghan

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Recently developed glucosylceramide synthase inhibitors with enhanced hydrophobicity display increased bioavailability in the central nervous system (CNS). Have these improvements come at a potential risk given that the improved glucosylceramide synthase inhibitors bear the hallmarks of P-glycoprotein substrates? This question warrants attention given the potential to induce adverse drug interactions or toxicity, if glucosylceramide synthase inhibitors are administered with other P-glycoprotein substrates. The aim of this study was to determine if glucosylceramide synthase inhibitors are substrates for the multidrug transporter P-glycoprotein. Direct measurements of glucosylceramide synthase inhibitors binding to P-glycoprotein were examined, as was their ability to modulate transport by the protein. The more hydrophobic glucosylceramide synthase inhibitors caused a reduction in drug binding to P-glycoprotein. However, the compounds did not achieve this by direct interaction with the protein, but through a general membrane perturbation. Furthermore, the alterations in drug-P-glycoprotein interaction did not manifest as altered cellular accumulation of glucosylceramide synthase inhibitors or altered efficacy to reduce cellular glycolipid levels. Consequently, P-glycoprotein expression will not contribute significantly to the pharmacokinetic profile of the iminosugar glucosylceramide synthase inhibitors.

Original languageEnglish
Pages (from-to)195-204
Number of pages10
JournalEuropean Journal of Pharmacology
Volume530
Issue number3
DOIs
Publication statusPublished - Jan 20 2006

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Keywords

  • Bioavailability
  • Deoxygalactonojirimycin
  • Drug transport
  • Glucosylceramide synthase inhibitor
  • Glycolipid
  • P-glycoprotein

ASJC Scopus subject areas

  • Pharmacology

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