Vanstraelen Kim, Wauters Joost, De Loor Henriette, Vercammen Ine, Annaert Pieter, Lagrou Katrien, Spriet Isabel
KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Clinical Pharmacology and Pharmacotherapy, University Hospitals Leuven, Leuven, 3000, Belgium.
J Pharm Sci. 2014 Aug;103(8):2565-70. doi: 10.1002/jps.24064. Epub 2014 Jun 24.
Plasma protein binding (PPB) can possibly alter the already variable pharmacokinetics of voriconazole. Voriconazole PPB was determined only once, being 58%, according to equilibrium dialysis (ED). We investigated voriconazole PPB more in detail, with a convenient and newer high-throughput ED assay (HT-ED), in human blank plasma spiked with voriconazole and in plasma from intensive care unit (ICU) patients treated with voriconazole. HT-ED was conducted in a 96-well plate, setup against phosphate-buffered saline. Voriconazole concentrations were measured by liquid chromatography-tandem mass spectrometry. The median PPB was 47.6% [interquartile range (IQR) 45.3%-50%] in vitro, and 49.6% (IQR 42.5%-52.5%) in ICU samples (p = 0.35), and is not depending on total voriconazole concentration (0.7-11.2 mg/L, p = 0.65). The drug mainly binds to albumin (25.5 ± 5.1%), and to a lesser extent to α-1-acid glycoprotein (AAG; 4.8 ± 1.2%). The HT-ED assay can be performed at 37 °C or 25 °C (p = 0.44) and in batch: PPB variations during freeze-thaw cycles (p = 0.13) and during frozen storage up to 12 months (p = 0.10) were not clinically relevant. Voriconazole PPB is approximately 50%, according to HT-ED. As albumin and AAG only account for approximately 30% of total voriconazole PPB, other plasma components could influence PPB and therefore efficacy or toxicity because of variations in unbound fractions.
血浆蛋白结合（PPB）可能会改变伏立康唑本就多变的药代动力学。根据平衡透析（ED）法，伏立康唑的血浆蛋白结合率仅测定过一次，为58%。我们使用一种便捷且更新的高通量平衡透析法（HT-ED），对添加了伏立康唑的人空白血浆以及接受伏立康唑治疗的重症监护病房（ICU）患者的血浆进行了更详细的伏立康唑血浆蛋白结合率研究。HT-ED在96孔板中进行，以磷酸盐缓冲盐水作为对照。伏立康唑浓度通过液相色谱-串联质谱法测定。体外实验中，血浆蛋白结合率中位数为47.6%[四分位间距（IQR）45.3%-50%]，在ICU样本中为49.6%（IQR 42.5%-52.5%）（p = 0.35），且不依赖于伏立康唑总浓度（0.7-11.2 mg/L，p = 0.65）。该药物主要与白蛋白结合（25.5 ± 5.1%），与α-1-酸性糖蛋白（AAG；4.8 ± 1.2%）的结合程度较低。HT-ED法可在37℃或25℃下进行（p = 0.44），且可批量操作：冻融循环期间（p = 0.13）以及长达12个月的冷冻储存期间（p = 0.10）的血浆蛋白结合率变化并无临床相关性。根据HT-ED法，伏立康唑的血浆蛋白结合率约为50%。由于白蛋白和AAG仅占伏立康唑总血浆蛋白结合率的约30%，其他血浆成分可能会因游离分数的变化而影响血浆蛋白结合率，进而影响疗效或毒性。
