The Impact of Plasma Protein Binding Characteristics and Unbound Concentration of Voriconazole on Its Adverse Drug Reactions

Abstract

This study investigated voriconazole (VRC) unbound plasma concentration and its relationship with adverse drug reactions (ADRs) in patients with malignant hematologic disease. Plasma samples were collected from patients or spiked in vitro. A time-saving rapid equilibrium dialysis assay was used for the separation of unbound and bound VRC, following a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis method for drug concentration detection. Liver function and treatment details were collected from the electronic medical records of patients. Protein concentration was determined according to instructions. VRC plasma protein binding rate (PPB) in patient is significantly higher [69.5 ± 6.2%] than that in in-vitro samples, influenced by total drug concentration (C t), plasma protein concentration, and protein type. The a1-acid glycogen (AAG) has the highest affinity with VRC. Relationship between total PPB of VRC with PPB of individual protein is not a simple addition, but a compressive combination. Unbound drug concentration (C u) of VRC shows significant relationships with C t , protein concentration, AST level, metabolism type of CYP2C19 and coadministration of high PPB medicines. Unbound plasma concentration of VRC shows a more sensitive relationship with ADRs than C t .

A Large Sample Retrospective Study on the Distinction of Voriconazole Concentration in Asian Patients from Different Clinical Departments

“…Kang et al found that ALT is a significant factor affecting VRZ concentration, in agreement with our results [32]. Although there is substantial evidence linking AST and VRZ concentration, we found no significant effect of AST in our model [33][34][35]. There are possible explanations for this.…”

Bacteroides Fragilis Polysaccharide A Ameliorates Abnormal Voriconazole Metabolism Accompanied With the Inhibition of TLR4/NF-κB Pathway

“…Here, there was still inter-individual variability in VRC concentrations and hepatotoxicity even among patients of the same metabolic type. In the past 2 decades, studies on the effects of treatment-related gastrointestinal changes, protein-binding changes, drug-drug interactions and even food intake on voriconazole metabolism have been reported ( Purkins et al, 2003 ; Hope et al, 2013 ; Yuan et al, 2020 ). While it has been shown that these physiological characteristics affect individual differences in response to voriconazole, the influence of inflammatory responses ( eg., CRP, IL-6) in combination with these physiological characteristics on the course of disease has not been investigated.…”

Comparison of Pinoresinol and its Diglucoside on their ADME Properties and Vasorelaxant Effects on Phenylephrine-Induced Model

“…The plasma protein binding rate of the samples was investigated using rapid equilibrium dialysis method ( Waters et al, 2008 ; Jiang C. et al, 2019 ; Yuan et al, 2020 ). In brief, the unbound drugs (or references) were separated from plasma (human and rat) in a 96-well plate with a semipermeable membrane through which only unbound drug can permeate.…”