Estimation of buspirone-bovine serum albumin binding by affinity capillary electrophoresis.

Drug-protein binding is an important process in pharmacokinetic phase of drug action. Capillary electrophoresis was employed, specifically the Hummel-Dreyer method and Scatchard analysis, to study the interactions of an anxiolytic drug, buspirone, with pure bovine serum albumin (BSA) and with BSA present in the human recombinant 5-HT(1A) serotonin receptor preparation. The binding constant of buspirone with BSA determined in free BSA solution was K = 5.55 x 10(4) M(-1) whereas its value with BSA present in the serotonin receptor preparation was K = 5.57 x 10(4) M(-1). The method was found to be inadequate for measuring the specific binding interactions between buspirone and the 5-HT(1A) receptor in the preparation employed.

Chromatographic modelling of interactions between melanin and phenothiazine and dibenzazepine drugs.

Differences in drug-melanin interactions were determined for 13 phenothiazine neuroleptics and 2 dibenzazepine thymoleptics by means of high-performance liquid chromatography. The chromatographic column was packed with a stationary phase obtained by chemical immobilization of synthetic L-dopa melanin on silica particles. For six phenothiazines the melanin-binding parameters were also determined by an ultrafiltration method. Correlation between measures of drug-melanin interaction determined chromatographically and by the standard slow-equilibrium method was significant, however moderate. The chromatographic method of assessing interactions between drugs and melanin permitted reliable and quantitatively comparable data for representative series of solutes to be readily obtained. Such data were subjected to the analysis of quantitative structure-retention relationships (QSRR). It was found that retention of the agents on the immobilized melanin column could be described by two-parameter regression equations comprising the energy of the lowest unoccupied molecular orbital and either the water-accessible surface area of a drug molecule or its hydrophobicity parameter, determined chromatographically on an immobilized artificial membrane column. The QSRR equation derived allows for the estimation of melanin binding based on the structure of a compound candidate, and thus rationalizes predictions of potential toxicity of drugs or drug candidates.

Mydriasis elicited by imidazol(in)e alpha 2-adrenomimetics in comparison with other adrenoceptor-mediated effects and hydrophobicity.

alpha 2-Adrenoceptor agonists cause both mydriasis and platelet aggregation. This work is aimed at identifying the factors accompanying and affecting mydriatic activity. For eight imidazol(in)e drugs mydriatic, hypotensive and bradycardic activities were determined in rats. The lipophilicity of the agents was determined chromatographically and calculated theoretically. A correlation was found between the hypotensive and the bradycardic potency and between the mydriatic activity and both the hypotensive and bradycardic activity. Mydriatic activity depended on the lipophilicity of the agents studied. The human platelet antiaggregatory activity of the drugs did not correlate with either the mydriatic or cardiovascular activity and it was independent of lipophilicity. The dependence of the centrally induced effects on lipophilicity and the lack of such a dependence in the case of the in vitro alpha 2-adrenoceptor-mediated platelet aggregation may be interpreted as resulting from heterogeneity of the rat cerebral and the human platelet alpha 2-adrenoceptors. The alpha 2-adrenergic activity of drugs in the model of mydriasis in rats cannot be predicted from their activity in causing human platelet aggregation in vitro.