Selective binding of imatinib to the genetic variants of human α1-acid glycoprotein

Imatinib binding to human serum albumin modulates heme association and reactivity

“…This study reports a detailed functional and structural characterization of imatinib binding to HSA, which may act as the secondary carrier of the drug in pathological states characterized by low plasma levels of AGP [20]; indeed AGP represents the first carrier of imatinib [7][8][9][10][11]13,66]. Moreover, the modulation of heme-Fe(III) binding to HSA and the reactivity of HSA-heme-Fe(III) by imatinib has been deeply investigated.…”

“…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].…”

Characterization of binding mode of imatinib to human α1-acid glycoprotein

“…clindamycin (CLI) and erythromycin, which are able to displace IMT bound to AGP. In an earlier study [27] we proved that the high-affinity and specific AGP binding of IMT belongs to the F1*S genetic variant. The association binding constant (K a ) value is 1.7(±0.2) × 10 6 M −1 and the found number of binding site (0.94) indicates no difference between the F1 and S variants.…”

Conformational landscape and low lying excited states of imatinib

“…From a spectroscopic point of view, IMT was studied previously by FT-IR and FT-Raman [33], NMR [34], mass spectrometry [35][36][37], HPLC [38][39][40][41][42][43], capillary electrophoresis [44,45] as well as by UV-vis in different solvents [17,32,33,[46][47][48]. Surprisingly, in spite of the importance of conformational space, to the best of our knowledge, only scarce data related to the conformers of IMT have been reported in the literature [19,23].…”