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  • Title: Study of interaction of carprofen and its enantiomers with human serum albumin--I. Mechanism of binding studied by dialysis and spectroscopic methods.
    Author: Rahman MH, Maruyama T, Okada T, Yamasaki K, Otagiri M.
    Journal: Biochem Pharmacol; 1993 Nov 17; 46(10):1721-31. PubMed ID: 7504487.
    Abstract:
    The binding of carprofen, a non-steroidal anti-inflammatory drug of the aryl propionic acid class [2-(6-chlorocarbazole)propionic acid], and its enantiomers to human serum albumin (HSA) has been studied by dialysis and spectroscopic methods. Binding parameters obtained by different methods were in close agreement. The binding of carprofen to HSA by both fluorescence and equilibrium dialysis (ED) methods is characterized by two sets of association constants [K1 = 5.1 x 10(6) M-1 (fluorescence) and 3.7 x 10(6) M-1 (ED), K2 = 3.7 x 10(5) M-1 (fluorescence) and 1.3 x 10(5) M-1 (ED)]. The S(+)-enantiomer of carprofen showed slightly higher affinity for HSA than its corresponding antipode by both methods. Different analyses of the binding to HSA suggested the presence of one high affinity site and five to seven low affinity sites for carprofen and its enantiomers on HSA. Fluorescence displacement data implied that carprofen primarily binds to site II, the benzodiazepine site, while the low affinity site of carprofen is site I, the warfarin site. Circular dichroism data suggested different mechanisms for the high affinity and the low affinity binding of carprofen to HSA. The data are consistent with the major part of the binding energy at site II being electrostatic and hydrophobic interactions, whereas for the low affinity binding, hydrophobic interactions. Binding was exothermic, entropy driven and spontaneous, as indicated by the thermodynamic analyses. From binding data with chemically modified HSA derivatives, it is likely that tyrosine, lysine and histidine residues are especially involved in carprofen binding to HSA, and it is most likely that the high affinity binding of carprofen is located in the N-terminal part of domain III or that section of protein plus the C-terminal part of domain II of the HSA molecule. When the binding of carprofen to HSA was compared to the binding of carprofen methyl ester to HSA (K = 0.1 x 10(6) M-1), the carboxyl group of carprofen was found to play an important role especially in the high affinity binding of carprofen to HSA. The high affinity of carprofen to HSA was independent of the conformational changes on HSA caused by N-B transition.
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