Effect of Diphenylhydantoin on the Metabolism of Metyrapone and Release of ACTH in Man

In this study it was demonstrated that the subnormal response to oral metyrapone in subjects treated with Dilantin results from decreased metyrapone blood levels which fail to inhibit 11β-hydroxylation adequately. The responses of plasma ACTH, cortisol, 11-deoxycortisol and urinary 17-OHCS were related to the plasma levels of unconjugated metyrapone in normal and diphenylhydantoin (Dilantin)-treated subjects. In patients chronically treated with Dilantin, the regular oral dose of metyrapone (750 mg every 4 hr for 6 doses) produced a significantly lower than normal plasma level of unconjugated metyrapone. Inhibition of 11β-hydroxylase estimated from the changes in plasma cortisol and 11-deoxycortisol was less than normal. The increases of plasma ACTH and urinary 17-OHCS in response to oral metyrapone were subnormal. When the regular oral dose of metyrapone was doubled (750 mg every 2 hr for 12 doses), the plasma levels of unconjugated metyrapone, ACTH and 11-deoxycortisol rose to the levels observed in normal subjects given the smaller regular dose. After intravenous administration of metyrapone, the end infusion plasma level and the rate of clearance from plasma were not significantly different in treated and untreated subjects. Intravenously administered metyrapone and bacterial pyrogen produced normal plasma ACTH and corticosteroid response in Dilantin-treated subjects.