Norris-Cervetto Edward, Butters Terry D, Martin Catherine, Modok Szabolcs, Dwek Raymond A, Callaghan Richard
Nuffield Department of Clinical Laboratory Sciences, Level 4, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
Eur J Pharmacol. 2006 Jan 20;530(3):195-204. doi: 10.1016/j.ejphar.2005.11.038. Epub 2006 Jan 3.
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.
最近开发的具有增强疏水性的葡萄糖神经酰胺合成酶抑制剂在中枢神经系统（CNS）中显示出更高的生物利用度。鉴于改良的葡萄糖神经酰胺合成酶抑制剂具有P-糖蛋白底物的特征，这些改进是否带来了潜在风险？如果葡萄糖神经酰胺合成酶抑制剂与其他P-糖蛋白底物一起给药，有可能引发药物相互作用或毒性，这个问题值得关注。本研究的目的是确定葡萄糖神经酰胺合成酶抑制剂是否为多药转运蛋白P-糖蛋白的底物。研究了对葡萄糖神经酰胺合成酶抑制剂与P-糖蛋白结合的直接测量，以及它们调节该蛋白转运的能力。疏水性更强的葡萄糖神经酰胺合成酶抑制剂导致药物与P-糖蛋白的结合减少。然而，这些化合物并非通过与该蛋白的直接相互作用来实现这一点，而是通过一般的膜扰动。此外，药物与P-糖蛋白相互作用的改变并未表现为葡萄糖神经酰胺合成酶抑制剂细胞内蓄积的改变或降低细胞糖脂水平功效的改变。因此，P-糖蛋白的表达对亚氨基糖葡萄糖神经酰胺合成酶抑制剂的药代动力学特征不会有显著影响。
