Optical, Structural and Thermodynamic Studies of the Association of an Anti-leucamic Drug Imatinib Mesylate with Transport Protein

Abstract

The interaction of an anti-leukemic drug, imatinib mesylate (IMT) with human serum albumin (HSA) was investigated by fluorescence, synchronous fluorescence, three-dimensional fluorescence, circular dichroism and UV-vis absorption techniques under physiological condition. The process of binding of IMT on HSA was observed to be through a spontaneous molecular interaction procedure. IMT effectively quenched the intrinsic fluorescence of HSA via static quenching. The values of binding constant, number of molecules that interact simultaneously with the binding site and thermodynamic parameters were evaluated by carrying out the interactions at three different temperatures. Based on thermodynamic parameters and displacement studies with site probes, it was proposed that the drug bound at Sudlow's site I of subdomain IIA. The change in the conformation of HSA was evident from synchronous, three-dimensional fluorescence and circular dichroism studies. The distance between the donor (protein) and acceptor (drug) was calculated based on the Foster's theory of resonance energy stransfer and it was found to be 1.30 nm. The effect of different metal ions on the binding of the drug to protein was also investigated.

Serum albumin and α-1 acid glycoprotein impede the killing of Schistosoma mansoni by the tyrosine kinase inhibitor Imatinib

“…Like SA, AGP has also been reported to bind to Imatinib, thus negatively influencing its therapeutic activity in cancer patients ( Kremer et al, 1988; Gambacorti-Passerini et al, 2000; Fitos et al, 2006, 2012; Hegde et al, 2012 ). To investigate the effect of AGP in our system, adult S. mansoni couples were maintained in culture medium, which was supplemented with human AGP at a final concentration of 0.8 g/L, similar to that found in human plasma (0.5–1.4 g/L) ( Schultz and Arnold, 1990; Gambacorti-Passerini et al, 2000 ).…”

“…To answer the question why the in vivo studies using Imatinib in the mouse and hamster models failed, we focused on SA and AGP as they are known to bind to drugs negatively influencing their action ( Piafsky, 1980; Kremer et al, 1988; Svensson et al, 1986 ). This includes Imatinib, which was reported to be bound by both of these major blood components ( Gambacorti-Passerini et al, 2000; Fitos et al, 2006, 2012; Hegde et al, 2012 ). Whereas no evidence was reported for a negative influence of HSA for Imatinib activity ( Hegde et al, 2012 ), there are controversial opinions about the consequences of its interaction with AGP.…”

“…This includes Imatinib, which was reported to be bound by both of these major blood components ( Gambacorti-Passerini et al, 2000; Fitos et al, 2006, 2012; Hegde et al, 2012 ). Whereas no evidence was reported for a negative influence of HSA for Imatinib activity ( Hegde et al, 2012 ), there are controversial opinions about the consequences of its interaction with AGP. Some studies describe a negative influence ( Gambacorti-Passerini et al, 2000, 2003; Azuma et al, 2007 ).…”

Imatinib binding to human serum albumin modulates heme association and reactivity

“…Previously, only imatinib binding to HSA was investigated [8,10,12]; values of the dissociation equilibrium constant for imatinib binding to HSA (i.e., K i ) reported in the literature and obtained by different methods [8,10,12,67] range between 4 Â 10 À6 M and 3 Â 10 À5 M. The value of the dissociation equilibrium constant here determined by competitive inhibition (i.e., K i ) is (9.6 ± 1.0) Â 10 À6 M, at 37.0°C and pH 7.0. Remarkably, the affinity of imatinib for HSA is lower than that for the Abl tyrosine kinases for which IC 50 values ranging from 2.5 Â 10 À8 M to 2.0 Â 10 À7 M have been reported (see [67] and references therein).…”

“…Indeed, HSA does not affect the pharmacokinetic properties of imatinib [8][9][10][11][12][13]. Accordingly, erythromycin, an AGP but not a HSA specific ligand, has been reported to increase the pharmacologically-active free fraction of imatinib in plasma [14].…”