Can P-glycoprotein influence the bioavailability of iminosugar-based glucosylceramide synthase inhibitors?
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.
Norris-Cervetto
Edward
E
Nuffield Department of Clinical Laboratory Sciences, Level 4, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Butters
Terry D
TD
Martin
Catherine
C
Modok
Szabolcs
S
Dwek
Raymond A
RA
Callaghan
Richard
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism; D001682:Biological Availability; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006017:Glycolipids / Q000378:metabolism; D006801:Humans; D050111:Imino Sugars; D014747:Vinblastine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D006017:Glycolipids; D050111:Imino Sugars; D014747:Vinblastine; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase