The Binding of Silibinin, the Main Constituent of Silymarin, to Site I on Human Serum Albumin

Abstract

Silibinin is the main constituent of silymarin, an extract from the seeds of milk thistle (Silybum marianum). Because silibinin has many pharmacological activities, extending its clinical use in the treatment of a wider variety of diseases would be desirable. In this study, we report on the binding of silibinin to plasma proteins, an issue that has not previously been extensively studied. The findings indicated that silibinin mainly binds to human serum albumin (HSA). Mutual displacement experiments using ligands that primarily bind to sites I and II clearly revealed that silibinin binds tightly and selectively to site I (subsites Ia and/or Ic) of HSA, which is located in subdomain IIA. Thermodynamic analyses suggested that hydrogen bonding and van der Waals interactions are major contributors to silibinin-HSA interactions. Furthermore, the binding of silibinin to HSA was found to be decreased with increasing ionic strength and detergent concentration of the media, suggesting that electrostatic and hydrophobic interactions are involved in the binding. Trp214 and Arg218 were identified as being involved in the binding of silibinin to site I, based on binding experiments using chemically modified-and mutant-HSAs. In conclusion, the available evidence indicates that silibinin binds to the region close to Trp214 and Arg218 in site I of HSA with assistance by multiple forces and can displace site I drugs (e.g., warfarin or iodipamide), but not site II drugs (e.g., ibuprofen).

Albumin-Encapsulated Liposomes: A Novel Drug Delivery Carrier With Hydrophobic Drugs Encapsulated in the Inner Aqueous Core

“…Two solvents, solvent A (50 mM sodium dihydrogen phosphate) and solvent B (50 mM sodium dihydrogen phosphate and acetonitrile, 30:70 v/v), were used for the analysis of WF, DZP, and SIL as the mobile phases. 11 The flow rate of the mobile phase was 1.0 mL/min at 40 C. The linear gradient elution of the solvents was programmed for the quantitation of each drug as follows: ). The fluorescence detector for WF analysis was fixed at excitation and emission wavelengths of 310 and 390 nm, respectively.…”

“…For this, we selected 4 different types (different molecular weight and binding site) of hydrophobic drugs (WF, DZP, PTX, and SIL), which are known to bind to albumin. 11,14,15 We first compared the solubility of the aforementioned hydrophobic drugs in ultrapure water and a 200 mg/mL solution of BSA. As a result, the solubility of WF, DZP, PTX, and SIL in the 200 mg/mL BSA solution was approximately 150-, 18-, 65-, and 8-fold higher than that for ultrapure water (Supplemental Fig.…”

Systematic review of pharmacokinetics and potential pharmacokinetic interactions of flavonolignans from silymarin

“…In rats, silybin is mainly bound to plasma TAG‐rich lipoproteins, 140 while in human plasma, it binds to a specific site on serum albumin 141,142 . The degree of plasma protein binding is significant.…”