PDF(Pubmed)
Abstract：
For antimicrobial agents in particular, plasma protein binding (PPB) plays a pivotal role in deciphering key properties of drug candidates. Animal models are generally used in the preclinical development of new drugs to predict their effects in humans using translational pharmacokinetics/pharmacodynamics (PK/PD). Thus, we compared the protein binding (PB) of cefazolin as well as bacterial growth under various conditions in vitro. The PB extent of cefazolin was studied in human, bovine, and rat plasmas at different antibiotic concentrations in buffer and media containing 20-70% plasma or pure plasma using ultrafiltration (UF) and equilibrium dialysis (ED). Moreover, bacterial growth and time-kill assays were performed in Mueller Hinton Broth (MHB) containing various plasma percentages. The pattern for cefazolin binding to plasma proteins was found to be similar for both UF and ED. There was a significant decrease in cefazolin binding to bovine plasma compared to human plasma, whereas the pattern in rat plasma was more consistent with that in human plasma. Our growth curve analysis revealed considerable growth inhibition of Escherichia coli at 70% bovine or rat plasma compared with 70% human plasma or pure MHB. As expected, our experiments with cefazolin at low concentrations showed that E. coli grew slightly better in 20% human and rat plasma compared to MHB, most probably due to cefazolin binding to proteins in the plasma. Based on the example of cefazolin, our study highlights the interspecies differences of PB with potential impact on PK/PD. These findings should be considered before preclinical PK/PD data can be extrapolated to human patients.
摘要：
特别是对于抗菌剂，血浆蛋白结合（PPB）在破译候选药物的关键特性中起着关键作用。动物模型通常用于新药的临床前开发中，以使用翻译药代动力学/药效学（PK/PD）预测其在人体中的作用。因此，我们比较了不同条件下头孢唑啉的蛋白质结合（PB）以及细菌在体外的生长。研究了头孢唑啉在人体中的PB水平，牛,使用超滤（UF）和平衡透析（ED），在缓冲液和含有20-70％血浆或纯血浆的培养基中使用不同抗生素浓度的大鼠血浆。此外，在含有各种血浆百分比的MuellerHinton肉汤（MHB）中进行细菌生长和时间杀伤测定。发现UF和ED的头孢唑啉与血浆蛋白结合的模式相似。与人血浆相比，头孢唑啉与牛血浆的结合显着降低，而大鼠血浆中的模式与人血浆中的模式更一致。我们的生长曲线分析显示，与70％人血浆或纯MHB相比，70％牛或大鼠血浆对大肠杆菌的生长具有相当大的抑制作用。不出所料,我们用低浓度的头孢唑啉进行的实验表明，与MHB相比，大肠杆菌在20％的人和大鼠血浆中的生长略好，很可能是由于头孢唑啉与血浆中的蛋白质结合。以头孢唑啉为例,我们的研究强调了PB的种间差异，对PK/PD有潜在影响。在将临床前PK/PD数据外推到人类患者之前，应考虑这些发现。
