Effect of subacute xylene administration on peripheral blood

Abstract

The ability of cyclosporin-A (CSA) and four of its metabolites M1, M17, M18 and M21, to inhibit antigen-stimulated release of β-hexoseaminidase from IgE-sensitized rat basophilic leukemia cells (RBL-2H3), as an in vitro correlate of anti-allergic effect, was studied. Metabolites 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 875.7ng/ml for CSA, M17 and Ml, respectively. M21 had approximately same IC50 as M1 while M18 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 relative anti-allergic potency of the metabolites was similar to their reported relative immunosuppressive potency. Combinations of low concentrations of CSA and its metabolites were synergistic in inhibiting enzyme release whereas at higher concentrations interactions were either additive 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 506 (3, 10 and 30ng/ml) and CSA (10, 30 and 100 ng/ml) or M 17 (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 compound, possess anti-allergic effects and that at concentrations that are obtainable in transplant patients, synergistic interaction occurs between CSA and its metabolites, and this may be of some therapeutic significance.