Flunisolide metabolism and dynamics of a metabolite

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Abstract
Flunisolide [FN] (6.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.,21-tetrahydroxypregna-1,4-diene-3,20-dione 16,17-acetonide) is a potent antiinflammatory corticoid used clinically in topical formulations. Men (3) were given single 2-mg i.v. and oral doses of 14C-labeled FN and plasma and urine concentrations of FN 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 FN was metabolized rapidly and extensively to the 6.beta.-OH metabolite and to conjugates; comparison in the i.v. dose kinetics suggested significant first-pass metabolism. In a separate study in 12 normal subjects, FN in plasma was quantitated by radioimmunoassay; average systemic availability was 20%. The apparent volume of distribution of FN 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 [HC] in rats as measured by thymolytic, anti-inflammatory and adrenal-suppressive assays, whereas FN had 180-550 .times. the activity of HC. These data offer a metabolic explanation for the clinical observation that FN can be administered intranasally and by inhalation in therapeutically effective doses without causing significant reduction in adrenal function.