Keita Y, Wörner W, Veile G, Woodcock B G, Fuhr U
Department of Clinical Pharmacology, Johann Wolfgang Goethe University, Frankfurt/Main, Germany.
Arzneimittelforschung. 1996 Feb;46(2):164-8.
The effect of a series of non-steroidal anti-inflammatory drugs (NSAIDs) on the binding kinetics of dansylsarcosine (CAS 72517-44-3, DS), a marker ligand for the benzodiazepine binding site, and human serum albumin (HSA) was studied using the stopped-flow method. Both native (7% glycated) and 25% glycated HSA were used. The binding parameters were determined on the basis of the consecutive model. The DS association rate constant (k2) was 649 +/- 84 s-1 and 375 +/- 13 s-1 for 7% and 25% glycated HSA, respectively. These values were substantially influenced by addition of NSAIDs (molar ratio HSA:NSAID = 2:1), depending on the structure of NSAIDs. The calculated DS dissociation rate constant (k-2) was approximately 20 s-1. this value did not show marked dependence on the degree of glycation or on the presence of NSAIDs at the concentration used. The values were similar to estimates of kd (the displacement rate constant of DS) with the exception of diclofenac (CAS 15307-86-5) where kd was significantly lower, reaching 4.8 +/- 0.4 s-1 and 4.8 +/- 0.6 s-1 vs. k-2 parameters of 14 +/- 2.8 s-1 and 15 +/- 3.7 s-1 for 7% and 25% glycated HSA, respectively. A comparison of the enantiomers R- and S-ibuprofen (CAS 15687-27-1) and the regioisomers fenbufen (CAS 36330-85-5) and ketoprofen (CAS 22071-15-4) showed slight or no stereoslectivity of effects on the DS binding kinetics. However, the binding was influenced by bulk and nature of substituents at the aryl rest of propionic acid. The results obtained for mefenamic acid (CAS 61-68-7) suggest that this NSAID binds to a site of human serum albumin other than site II. Increased concentrations of glycoalbumin, as observed in diabetic patients, are not presumed to have inhibitory effects additional to that of NSAIDs which interact differentially with drugs at site II of HSA.
采用停流法研究了一系列非甾体抗炎药（NSAIDs）对丹磺酰肌氨酸（CAS 72517-44-3，DS）与人类血清白蛋白（HSA）结合动力学的影响。DS是苯二氮䓬结合位点的标记配体。使用了天然（7%糖化）和25%糖化的HSA。基于连续模型确定结合参数。对于7%和25%糖化的HSA，DS缔合速率常数（k2）分别为649±84 s-1和375±13 s-1。这些值受到NSAIDs添加量（HSA与NSAIDs的摩尔比为2:1）的显著影响，具体取决于NSAIDs的结构。计算得到的DS解离速率常数（k-2）约为20 s-1。该值对糖化程度或所用浓度下NSAIDs的存在没有明显依赖性。除双氯芬酸（CAS 15307-86-5）外，这些值与kd（DS的置换速率常数）的估计值相似，双氯芬酸的kd显著更低，对于7%和25%糖化的HSA，kd分别为4.8±0.4 s-1和4.8±0.6 s-1，而k-2参数分别为14±2.8 s-1和15±3.7 s-1。对R-和S-布洛芬（CAS 15687-27-1）对映体以及非诺洛芬（CAS 36330-85-5）和酮洛芬（CAS 22071-15-4）区域异构体的比较表明，它们对DS结合动力学的影响具有轻微或无立体选择性。然而，结合受到丙酸芳基部分取代基的体积和性质的影响。甲芬那酸（CAS 61-68-7）的结果表明，这种NSAIDs与人血清白蛋白的结合位点不是位点II。在糖尿病患者中观察到的糖基化白蛋白浓度增加，除了NSAIDs与HSA位点II上的药物有不同相互作用外，预计不会有额外的抑制作用。
