ANTIALLERGIC ACTIVITY OF CYCLOSPORINE-A METABOLITES AND THEIR INTERACTION WITH THE PARENT COMPOUND AND FK-506

The ability of cyclosporin-A (CSA) and four of its metabolites M1, M17 , M18 and M21, to inhibit antigen-stimulated release of beta-hexoseami nidase from IgE-sensitized rat basophilic leukemia cells (RBL-2H3), as an in vitro correlate of anti-allergic effect, was studied. Metabolit es M17, M1 and M21 were effective in inhibiting enzyme release, though less potent than the parent compound. The concentrations achieving 50 % inhibition (IC50 values) were 53.3, 315.5 and 875.7 ng/ml for CSA, M 17 and M1, respectively. M21 had approximately same IC50 as M1 while M 18 was essentially inactive. At the highest concentration tested (1000 ng/ml) the mean maximum percentage inhibitions were 98.6, 79.5, 53.9, 48.6 and 12.2 for CSA, M17, M1, M21 and M18, respectively. The relati ve anti-allergic potency of the metabolites was similar to their repor ted relative immunosuppressive potency. Combinations of low concentrat ions of CSA and its metabolites were synergistic in inhibiting enzyme release whereas at higher concentrations interactions were either addi tive or antagonistic. Even the concentrations of the metabolites that have little or no activity when used alone also potentiated the effect of CSA. The immunosuppressor FK 506 was found to be about three times more potent than CSA in this system and the interactions between FK 5 06 (3, 10 and 30 ng/ml) and CSA (10, 30 and 100 ng/ml) or M17 (20, 100 and 500 ng/ml) were synergistic at all combinations. Both CSA and M17 synergized more strongly with FK 506 than they did between themselves . These results show that some metabolites of CSA, like the parent com pound, possess anti-allergic effects and that at concentrations that a re obtainable in transplant patients, synergistic interaction occurs b etween CSA and its metabolites, and this may be of some therapeutic si gnificance. Copyright (C) 1996 International Society for Immunopharmac ology.