pH-dependent degradation and stabilization of meclofenoxate hydrochloride by human serum albumin.

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Abstract
The hydrolysis rate of meclofenoxate hydrochloride (MFX) was investigated in the absence and in the presence of human serum albumin (HSA). Compared with the degradation of the drug (pKa 8.2) in buffer solutions, the degradation rate in HSA solutions (pH 4.0-10.7) was accelerated in the acidic region below pH 7.0 and was retarded in the basic region above pH 7.0. Based on a Michaelis-Menten type kinetic scheme involving the formation of HSA-drug complexes for both prontonated and neutral forms of MFX, the effects of the protein on the degradation rate were analyzed and the hydrolysis rate constants and the binding constants of HSA-drug complexes were obtained. It was found that the neutral form was considerably stabilized by the association with HSA whereas the degradation of the protonated form was accelerated, and the neutral form-HSA complex was extremely stable compared with the protonated form-HSA complex. Theses results suggest that the neutral and protonated forms are bound to HSA molecules in different modes, the former being less accessible than the latter to hdyroxide ion attack.