Quantitative correlations between albumin binding constants and chromatographic RM values of phenothiazine derivatives

Abstract

The binding constants of 15 phenothiazine derivatives [triflupromazine, promazine, chlorpromazine, methopromazine, methylpromazine, cyanopromazine, thioridazine, propericazine, mesoridazine, perazine, trifluoperazine, prochlorperazine, butaperazine, dixyrazine, fluphenazine, perphenazine] to bovine serum albumin were obtained by a circular dichroic probe technique. The lipophilicity of the drugs, measured by a reversed-phase thin-layer technique using oleyl alcohol and methanol-water mixtures as the solvents, is expressed as as RMw. The binding constants were of the same order of magnitude as the literature values and the RMw values correlated well with log Poctanol values from the literature. Correlations of log K with RMw were more satisfactory when corrections for the state of ionization of the phenothiazines were made, the nonprotonated species accounting for the bulk of the binding. A better correlation was obtained when contributions from both species were taken into account. Similar correlations were attempted between RMw values and enzyme inhibitory activities of these phenothiazines taken from the literature. [Rat mast cell histamine release and antihemolytic activity in dogs are discussed.].