Metabolism and Effect on Pituitary-adrenal Cortex of Injectable Dexamethasone

Abstract

The metabolic fate and pituitary-adrenal cortex-supressibility of two injectable dexamethasone esters, 21-phosphate and 21-sulfate, were studied in ten healthy men. After i. v. injection in a dose of 20 mg free steroid alcohol, dexamethasone phosphate was efficiently hydrolyzed to free dexamethasone, reaching its peak plasma concentration within 5 minutes. 20-Dihydrodexamethasone, a metabolite of dexamethasone, reached its peak plasma concentration 2 hours after injection. About 6% of administered dose appeared in 24 hours urine as free dexamethasone. By contrast, virtually no free dexamethasone and 20-dihydrodexamethasone were found in plasma and urine after dexamethasone sulfate injection. Pharmacokinetic analysis showed that dexamethasone sulfate had shorter plasma half-life and greater metabolic clearance rate than did free dexamethasone. A large fraction (63%) of dexamethasone sulfate was quickly excreted unmetabolized in urine.Plasma cortisol level was significantly supressed over 24 hours after dexamethasone phosphate, while the plasma cortisol profile after dexamethasone sulfate showed mere physiological circadian variations. When the steroid esters were injected after pretreatment with metyrapone, a definite supression of plasma ACTH was noted after dexamethasone phosphate. Here again, dexamethasone sulfate was ineffective.The results cast a serious doubt on the clinical value of dexamethasone sulfate as an injectable glucocorticoid, and critical reevaluation on this preparation is needed.