title: Protein-binding characteristics of voriconazole determined by high-throughput equilibrium dialysis.
abstract: 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.
authors: KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Clinical Pharmacology and Pharmacotherapy, University Hospitals Leuven, Leuven, 3000, Belgium.
authors: Kim
authors: K
authors: Vanstraelen
authors: Joost
authors: J
authors: Wauters
authors: Henriette
authors: H
authors: De Loor
authors: Ine
authors: I
authors: Vercammen
authors: Pieter
authors: P
authors: Annaert
authors: Katrien
authors: K
authors: Lagrou
authors: Isabel
authors: I
authors: Spriet
mesh_terms: D000935:Antifungal Agents / Q000097:blood / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism*; D002853:Chromatography, Liquid; D003956:Dialysis; D057166:High-Throughput Screening Assays; D006801:Humans; D013058:Mass Spectrometry; D009961:Orosomucoid / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D065819:Voriconazole / Q000097:blood / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D001798:Blood Proteins; D009961:Orosomucoid; D012709:Serum Albumin; D065819:Voriconazole
keywords: albumin; equilibrium dialysis; high-throughput technologies; pharmacokinetics; protein binding; unbound fraction; voriconazole; α-1-acid-glycoprotein