Interactions of Linezolid with Two Major Serum Proteins, Human Serum Albumin and Alpha-1 Acid Glycoprotein

Linezolid (LZD) is an oxazolidinone antibiotic agent that acts against gram-positive bacteria. It was recently reported that LZD can induce severe hematologic toxicity, which is thought to result in high LZD concentrations in plasma. Although many factors can affect the disposition of drugs, the binding of drug to plasma proteins, such as albumin and alpha1-acid glycoprotein (AGP), is one of the most important factors due to the competitive displacement of drugs from proteins. However, little is known about the interactions of LZD with these proteins. The aim of this study was to elucidate the binding characteristics of LZD to human serum albumin (HSA) and AGP, including binding parameters and the binding site. Based on the results of fluorescence studies and ultrafiltration experiments, it appears that LZD binds to both HSA and AGP, but the affinity of LZD for both proteins was low. Competitive protein binding analyses using an ultrafilitration method clearly indicated that LZD binds to the digitoxin binding site on HSA and the basic and/or hydrophobic drug binding site on AGP. These detailed analyses of LZD-HSA or LZD-AGP interactions provide valuable information in terms of understanding the pharmacokinetics properties of LZD in clinical settings.