The efficacy of certain anti-tuberculosis drugs is affected by binding to α-1-acid glycoprotein
The efficacy of certain anti-tuberculosis drugs is affected by binding to α-1-acid glycoprotein
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DOI：
10.1002/bmc.641
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发表时间：
2006-06-01
影响因子：
1.8
通讯作者：
Smith, Kevin D.
中科院分区：
文献类型：
--
作者：
Johnson, Deborah-Ann;Smith, Kevin D.
α-1-酸性糖蛋白 (AGP) 是最普遍存在的血浆蛋白之一，对生理 pH 值下带正电的碱性药物具有高亲和力、低容量结合能力。此外，作为一种急性期蛋白，其水平在各种疾病状态下增加，其方式可能影响药物的游离血浆水平、达到最低有效浓度的能力和总体体内有效性。 AGP 是一种已知会显示疾病特异性糖基化变化的糖蛋白，虽然这种二次修饰不直接参与药物结合，但它可能会影响结合位点的构象。结合研究表明，α-1-酸性糖蛋白主要与结核病药物结合：利福平；异烟肼；吡嗪酰胺；帕氨基水杨酸；卷曲霉素；乙硫异烟胺；左氧氟沙星和氧氟沙星在治疗血浆范围内进行了测试。然而，这些结果仍然被认为是重要的，因为不仅在急性期反应期间α-1-酸性糖蛋白水平增加，而且来自结核病样品的特定α-1-酸性糖蛋白发生糖基化变化，这可以增加结合亲和力并导致在治疗浓度下发生结合。版权所有 (c) 2006 John Wiley & Sons, Ltd.
One of the most ubiquitous plasma proteins, alpha-1-acid glycoprotein (AGP), has a high affinity, low capacity binding for basic drugs positively charged at physiological pH. Moreover, as an acute phase protein its level is increased in various disease states in a manner that is likely to influence the free plasma level of a drug, the ability to attain minimum effective concentration and overall in vivo effectiveness. AGP is a glycoprotein known to display disease specific changes in glycosylation and although this secondary modification is not directly involved in drug binding, it may influence the conformation of the binding site. Binding studies reveal that alpha-1-acid glycoprotein bind mainly to the tuberculosis drugs: rifampicin; isoniazid; pyrazinamide; paminosalicylic acid; capreomycin; ethionamide; levofloxacin and ofloxacin out with the therapeutic plasma range tested. These results are however still considered significant as not only are alpha-1-acid glycoprotein levels increased during the acute phase response but specific alpha-1-acid glycoprotein from tuberculosis samples are subject to glycosylation changes which can increase the binding affinity and cause binding to occur at the therapeutic concentration. Copyright (c) 2006 John Wiley & Sons, Ltd.