loteprednol-etabonate and cortienic-acid

Topics: Administration, Topical; Adrenal Cortex Hormones; Androstadienes; Androstenediols; Animals; Dogs; Drug Design; Drug Evaluation; Humans; Hydrolysis; Inactivation, Metabolic; Loteprednol Etabonate; Models, Molecular; Molecular Structure; Rabbits; Rats; Structure-Activity Relationship

An improved synthesis of loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene 17 beta-carboxylate) was achieved. The design of the new type of glucocorticoid was based on the soft drug concept. The relative binding affinities of loteprednol and its putative metabolites (PJ90 and PJ91) to rat lung type II glucocorticoid receptor were determined in a competitive binding experiment with [3H]triamicinolone acetonide. The medium contained cortienic acid (10(-5) M) in order to block transcortin binding sites. Loteprednol etabonate exhibited a binding affinity which was 4.3 times that of dexamethasone, both compounds having a Hill factor close to 1 whereas PJ90 and PJ91 did not show any affinity to the receptor. Loteprednol etabonate was compared to betamethasone 17 alpha-valerate in a vasoconstriction test which was performed on the forearm skin of human volunteers. The results showed that loteprednol etabonate has good skin-permeation properties and strong glucocorticoid activity.

Topics: Androstadienes; Androstenediols; Animals; Binding, Competitive; Dexamethasone; Drug Design; Loteprednol Etabonate; Lung; Male; Rats; Rats, Inbred Strains; Receptors, Glucocorticoid; Transcortin; Tritium; Vasoconstriction