Flunisolide metabolism and dynamics of a metabolite

Flunisolide (6 alpha-fluoro-11 beta,16 alpha,17 alpha,21-tetrahydroxypregna-1,4-diene-3,20-dione 16,17-acetonide) is a potent corticoid used clinically in topical formulations. Three men were given single 2-mg intravenous and oral doses of 14C-labeled flunisolide and plasma and urine concentrations of flunisolide and a major metabolite, 6 beta,11 beta,16 alpha,17 alpha,21-penta-hydroxypregna-1,4-diene-3,20-dione 16,17-acetonide (6 beta-OH metabolite) were determined. Oral flunisolide was metabolized rapidly and extensively to the 6 beta-OH metabolite and to conjugates; comparison in the intravenous dose kinetics suggested significant first-pass metabolism. In a separate study in 12 normal subjects, flunisolide in plasma was quantitated by radioimmunoassay (RIA); average systemic availability was 20%. The apparent volume of distribution (Vd beta) of flunisolide was large and systemic clearance and apparent oral clearance values were high. The 6 beta-OH metabolite had corticoid activities no more than 3 times that of hydrocortisone in rats as measured by thymolytic, anti-inflammatory, and adrenal-suppressive assays, whereas flunisolide had 180 to 550 times the activity of hydrocortisone. These data offer a metabolic explanation for the clinical observation that flunisolide can be administered intranasally and by inhalation in therapeutically effective doses without causing significant reduction in adrenal function.