Comparison of the histamine-releasing activity of cremophor E1 and some of its derivatives in two experimental models: the in vivo anaesthetized dog and in vitro rat peritoneal mast cells.

Histamine release caused by drugs and/or their solvents in clinical conditions is a well documented observation but the mechanism of this reaction is poorly understood. Hence in this study, the histamine releasing ability of cremophor E1 and six derivatives of 12-hydroxystearic acid (12-HSA) were compared in two models: the in vivo anaesthetized dog and the in vitro isolated rat peritoneal mast cells. The results obtained in both systems differed markedly. Only one compound DH (the diester of 12-HSA with polyethylene glycol) released histamine in both systems. The two substances, which exhibited the weakest histamine releasing ability in the dog model (almost inactive at the doses given) were powerful releasers of histamine from rat peritoneal mast cells (TN, 12-HSA polymerized with ethylene oxide; and ME, the monoester of 12-HSA esterified with polyethylene glycol). The release of histamine from rat peritoneal mast cells was potentiated as the temperature was elevated above 37 degrees C. Due to the heterogeneity of mast cells from both different species and different tissues in the same animal, it is important to choose the appropriate predictive model for clinically important adverse reactions to drugs and/or their solvents. Agents which release histamine by non-specific mechanisms are not uninteresting for the clinical situation.