Warfarin/human serum albumin binding

Kraak et al. (38) reported the first ACE application to study drug binding to a plasma protein. They used the model system warfarin-human serum albumin (HSA) to compare the suitability of the Hummel-Dreyer, frontal analysis, and vacancy peak methods. A more methodologically intended paper from Erim and Kraak (39) used VACE to study the displacement of warfarin from bovine serum albumin (BSA) by furosemide and phenylbutazone. They concluded that VACE is especially suited to examining competitive properties of simultaneously administered compounds toward a given protein-drug system. 

Pinkerton TC, Koeplinger KA (1990) Determination of warfarin-human serum albumin protein binding parameters by an improved Hummel-Dreyer high performance liquid chromatography method using internal surface reversed-phase columns. Anal Chem 62 2114-2122. 

Twine, S., East, M., and Curry, S. Crystal structure analysis of warfarin binding to human serum albumin. Anatomy of dmg site I. /. Biol. Chem. 

The Ki for HSA binding to racemic warfarin has been reported for 3-6 pM by various techniques, including frontal analysis and equilibrium dialysis, and is temperature- and pH-dependent. See Loun, B., Hage, D.S. Chiral separation mechanisms in protein-based HPLC columns. 1. Thermodynamic studies of (R)- and (S)-warfarin binding to immobilized human serum albumin. Anal. Chem. 1994, 66, 3814-3822. 

The frontal analysis technique has been used for the determination of enantioselective binding constants of chiral drugs such as warfarin, verapamil, nilvadipine, and semotidil with proteins such as bovine serum albumin (BSA), human serum albumin (HSA), and plasma lipoproteins (45-51). 

K. J. Fehske, U. Schlafer, U. WoUert, and W. E. Muller, Characterization of an important drug binding area on human serum albumin, including the high-affinity binding sites of warfarin and azapropazone. Mo/. Pharmacd., 21 387 (1982). 

E. Domenici, C. Bertucd, F Salvadori, and I. W. Wainer, Use of a human serum albumin-based chiral stationary phase for high performance liquid chromatography for the investigation of protein binding Detection of the allosteric interaction between warfarin and benzodiazepine binding sites, /. Pharm. Set., 80 164 (1991). 

K. Veronich, G, White, and A. Kapoor, Effects of phenylbutazone, tolbutamide and clofibric add on binding of racemic warfarin and its enantiomers to human serum albumin, J. Pharm. Sci., 68 1515 (1979). 

B. SebiUe, N. Thuaud, J. F TiUement, and J. Brienne, Effect of long chain free fatty adds on the conformation of the human serum albumin warfarin binding site as studied by circular dichroism, Inl. ]. Bid. Macromd., 6 175 (1984). 

I, Fitos, M. Simonyi, and Z. Tegyey, Resolution of warfarin via enhanced stereoselective binding to human serum albumin induced by lorazepam acetate. Chromatography 87 (H. Kalasz and L. S, Ettre, eds.), Akademiai Kiado, Budapest, 1988, p. 205,... 

I. Fitos, C. Lagercrantz, T. Larsson, M. Simonyi, I. Sjoholm, and Z. Tegyey, Stereoselective binding of 3-acetoxy-l,4-benzodiazepin-2-ones and 3-hydroxy-l,4-benzodi epin-2-ones to human serum albumin Selective allosteric interaction with warfarin enantiomers, Biodiem. Pharmacol., 35 263 (1986). 

I. Fitos, Z, Tegyey, M. Simonyi, and M. Kajtar, Stereoselective allosteric interaction in the binding of lorazepam methylether and warfarin to human serum albumin, Bio-Orgartic Heterocycles 1986 Synthesis, Mechanisms and Bioactivity (H. C. van der Plas, M, Simonyi, E C. Alderweireidt, and J. A. Lepoivre, eds.), Elsevier, Amsterdam, 1986, p. 275,... 

I. Fitos and M. Simonyi, Selective effect of clonazepam and (S)-uxepam on the binding of warfarin enantiomers to human serum albumin, /. Chroma-togr., 450 217 (1988). 

I. Fitos, J. Visy, A. Magyar, J. Kajtar, and M. Simonyi, Stereoselective effect of warfarin and bilirubin on the binding of 5-(o-chlorophenyl)-l,3-dihydro-3-methyl-7-nttro-2H-l,4-benzodiazepin-2-one enantiomers to human serum albumin. Chirality, 2 161 (1990). 

Zini, R. D Athis, P. Barre, J. Tillement, J.P. Binding of indomethacin to human serum albumin its non-displacment by various agents, influence of free fatty acid and the unexpected effect of indomethacin on warfarin. Biochem. Pharmacol. 1979, 28, 2661-2665. 

Etacrynic acid interacts with human serum albumin and modifies its binding properties (45). Since it binds to two binding sites on albumin, the benzodiazepine binding site and the warfarin binding site, it can displace drugs that bind at those sites (46). It competitively displaced 7-hydroxymethotrexate from its binding proteins in vitro (47). The clinical significance of this effect is not known. 

Plasma albumin has binding sites for various natural metabolic substances (e.g., glucose, fatty acids, bilirubin) as well as xenobiotics and drugs (e.g., digitoxin, Warfarin). While chromatographic and solubility differences from pure human serum albumin occur in some glycosylated albumins, there does... 

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