Comparative study of anti-endotoxic potency of dexamethasone based on its different ester types.

Difference in the anti-endotoxic potency in mice between dexamethasone 21-disodium phosphate (DM-P) and 21-sodium sulfate (DM-S) was investigated. Changes in the plasma levels of free 17-hydroxycorticoids (17-OHCS), further, were defined after intravenous administration of 2 mg/kg dexamethasone in elective surgical patients for elucidation of the metabolic basis of the different anti-endotoxic potencies of the two ester types of dexamethasone. Young male mice of DDN strain were pretreated with 0.2 mg DM-P or DM-S. Following the pretreatment, 0.5 mg of the endotoxin was administered at varying intervals of 0--24 hours, and survival rates were determined after 72 hours. In the DM-P group the mice exhibited a significant resistance to the endotoxin within two hours after the pretreatment, but in the DM-S group, the mice exhibited no anti-endotoxic potency. When different doses of dexamethasone (from 3.2 to 0.00625 mg) were administered with 0.5 mg of the endotoxin simultaneously, the mice in the DM-P group showed improvements in survival rates that tended to be dose related, but the mice in DM-S group showed no improvement in survival rates. Plasma levels of free 17-OHCS in elective surgical patients, further, were remarkably elevated after administration of DM-P, 2 mg/kg, but they showed no elevation after administration of DM-S, 2 mg/kg. Thus, it is clear that the in vivo metabolism of the two esters is different. DM-P easily liberates its free form, whereas DM-S does not. From this evidence, it was concluded that there is a close correlation between the anti-endotoxic potency of dexamethasone and its plasma level of free form, and that glucocorticoids can demonstrate their anti-endotoxic action when they are present at pharmacologically high levels in the bloodstream. There is considerable difference in biological action, moreover, between the two water-soluble esters of dexamethasone. More attention should be paid to this difference when investigating the treatment of shock with glucocorticoids.