Studies on Dexamethasone Metabolism in Man: Effect of Diphenylhydantoin

Abstract

Plasma kinetics and metabolism of labeled dexamethasone were evaluated in nine subjects before and after administration of diphenylhydantoin. Labeled dexamethasone was injected intravenously followed by frequent sampling of blood and urine. The labeled dexamethasone in plasma was isolated chromatographically. Total urine and fractional radioactivity after solvent extraction (chloroform and ethyl acetate), with and without glucuronide hydrolysis, were determined. Baseline plasma equilibrated t½'s and metabolic clearance rates (2 compartment model) ranged from 167 to 368 minutes and 222 to 456 liters/day, respectively. After diphenylhydantoin there were consistent decreases in t½'s and increases in metabolic clearance rate; mean changes —51% and +140% respectively. Mean recovery of urinary radioactivity at 4 and 24 hours was 16 and 64 percent of dose respectively. The largest fraction was a more polar unconjugated one, 7 and 31 percent of dose at 4 and 24 hours. Following diphenylhydantoin there was a significant increase in rate of appearance of radioactivity in urine, the greatest increase being in the more polar unconjugated fraction. It is concluded that 1) the metabolic kinetics of plasma dexamethasone vary considerably among individuals and 2) diphenylhydantoin administration markedly hastens removal rate of dexamethasone from plasma mainly by increasing conversion to more polar metabolites.