Modulation of histamine release from rat peritoneal mast cells by non-cytotoxic concentrations of the detergents Cremophor El® (oxethylated castor oil) and Triton X100. A possible explanation for unexpected adverse drug reactions?

Abstract

Clinically relevant histamine release caused by drugs and/or their solvents is a well known phenomenon. The mechanisms whereby these reactions occur are largely unknown. It was thought that the solubilizing agents potentiate the histamine release elicited by the drugs. Therefore the ability of the two detergents, Cremophor El and Triton X100, to modulate histamine release from rat peritoneal mast cells was examined. Both detergents were used in concentrations that did not themselves induce histamine release. The addition of the detergents to incubation media containing compound 48/80 (0.1 microgram/ml) elevated the release considerably (48/80 alone = 16.2 +/- 2.1% (n = 3); plus Cremophor El (5%) = 41.1 +/- 3.3% (n = 4); plus Triton X100 (0.02 microliter/ml) = 39.7 +/- 3.9% (n = 3); plus Triton X100 (0.01 microliter/ml) = 33.4 +/- 5.0% (n = 3)). In contrast, histamine release induced by Concanavalin A or the calcium ionophore A 23187 was inhibited by both detergents. Thus low concentrations of detergents appear to have a dual role, with both potentiation and inhibition of histamine release being observed. Surgical patients receive many drugs, some soluble in aqueous solutions, others only with the aid of solubilizing agents. 'Hangover effects' due to different plasma half lives, may therefore cause a seemingly harmless drug to act as a histamine liberator. It is therefore important to examine the action of clinically used solvents on histamine liberation caused by therapeutic agents, in order to gain a further understanding of the reaction mechanisms of adverse reactions to drugs.