Seedher Neelam, Kanojia Mamta
Department of Chemistry, Panjab University, Chandigarh 160014, India.
Drug Metabol Drug Interact. 2013;28(2):107-14. doi: 10.1515/dmdi-2012-0044.
The hypoglycemic effect of antidiabetic drugs varies with change in the level of endogenous substances in the body in diseased states largely due to alteration in drug-serum albumin binding affinity. The aim of the present study was to understand and quantify this effect.
Quenching of intrinsic fluorescence of human serum albumin was used to monitor the competitive binding of antidiabetic drugs (gliclazide, glimepiride, glipizide and repaglinide) and bilirubin/hemin/chloride ions.
Bilirubin and hemin were bound at site I and site II in human serum albumin with association constants of the order of 105. The presence of bilirubin decreased the binding affinity of all the antidiabetic drugs. In the presence of hemin, the binding of gliclazide and glimepiride increased significantly, whereas that of glipizide and repaglinide decreased. The presence of chloride ions decreased the association constants of all drugs except glimepiride. More than 20% increase in the percentage of free drug was observed for gliclazide in the presence of bilirubin and for repaglinide in the presence of bilirubin and hemin. A large decrease was also observed in the percentage of free gliclazide in the presence of hemin, and free glimepiride in the presence of hemin and chloride ions. Competitive binding mechanism has also been proposed. Significant changes (increase/decrease) in the availability of free pharmacologically active antidiabetic drugs, observed in some cases, can result in fluctuations in the blood glucose level of diabetic patients. The effect, which varied with the nature of the drug and the competing substance, was relatively large for gliclazide and repaglinide compared to other drugs.
抗糖尿病药物的降血糖作用会因疾病状态下体内内源性物质水平的变化而有所不同，这主要是由于药物与血清白蛋白结合亲和力的改变。本研究的目的是了解并量化这种效应。
利用人血清白蛋白的内源荧光猝灭来监测抗糖尿病药物（格列齐特、格列美脲、格列吡嗪和瑞格列奈）与胆红素/血红素/氯离子的竞争性结合。
胆红素和血红素与人血清白蛋白的位点I和位点II结合，缔合常数约为105。胆红素的存在降低了所有抗糖尿病药物的结合亲和力。在血红素存在的情况下，格列齐特和格列美脲的结合显著增加，而格列吡嗪和瑞格列奈的结合则减少。氯离子的存在降低了除格列美脲外所有药物的缔合常数。在胆红素存在的情况下，格列齐特的游离药物百分比增加了20%以上；在胆红素和血红素存在的情况下，瑞格列奈的游离药物百分比也增加了20%以上。在血红素存在的情况下，格列齐特的游离药物百分比大幅下降；在血红素和氯离子存在的情况下，格列美脲的游离药物百分比也大幅下降。还提出了竞争性结合机制。在某些情况下，观察到游离的具有药理活性的抗糖尿病药物可用性发生显著变化（增加/减少），这可能导致糖尿病患者血糖水平的波动。与其他药物相比，格列齐特和瑞格列奈的这种效应因药物和竞争物质的性质而异，相对较大。
