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-glycoprote...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2006
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| _version_ | 1826291241048866816 |
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| author | Norris-Cervetto, E Butters, T Martin, C Modok, S Dwek, R Callaghan, R |
| author_facet | Norris-Cervetto, E Butters, T Martin, C Modok, S Dwek, R Callaghan, R |
| author_sort | Norris-Cervetto, E |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T02:56:28Z |
| format | Journal article |
| id | oxford-uuid:af739c28-cff9-4f64-9d2d-2028ce5484ef |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:56:28Z |
| publishDate | 2006 |
| record_format | dspace |
| spelling | oxford-uuid:af739c28-cff9-4f64-9d2d-2028ce5484ef2022-03-27T03:49:39ZCan P-glycoprotein influence the bioavailability of iminosugar-based glucosylceramide synthase inhibitors?Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:af739c28-cff9-4f64-9d2d-2028ce5484efEnglishSymplectic Elements at Oxford2006Norris-Cervetto, EButters, TMartin, CModok, SDwek, RCallaghan, RRecently 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. |
| spellingShingle | Norris-Cervetto, E Butters, T Martin, C Modok, S Dwek, R Callaghan, R Can P-glycoprotein influence the bioavailability of iminosugar-based glucosylceramide synthase inhibitors? |
| title | Can P-glycoprotein influence the bioavailability of iminosugar-based glucosylceramide synthase inhibitors? |
| title_full | Can P-glycoprotein influence the bioavailability of iminosugar-based glucosylceramide synthase inhibitors? |
| title_fullStr | Can P-glycoprotein influence the bioavailability of iminosugar-based glucosylceramide synthase inhibitors? |
| title_full_unstemmed | Can P-glycoprotein influence the bioavailability of iminosugar-based glucosylceramide synthase inhibitors? |
| title_short | Can P-glycoprotein influence the bioavailability of iminosugar-based glucosylceramide synthase inhibitors? |
| title_sort | can p glycoprotein influence the bioavailability of iminosugar based glucosylceramide synthase inhibitors |
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