Disposition of flunisolide in the rat, mouse, dog, rhesus monkey, and cynomolgus monkey

Flunisolide (6 alpha-fluoro-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxypregna-1,4-diene-3,20-dione 16,17-acetonide) administered as a single iv or oral dose to rats, mice, dogs, rhesus monkeys, and cynomolgus monkeys had a plasma t 1/2 of 1-3.5 hr and was eliminated mainly via the bile. After iv administration of 14C-labeled flunisolide, radioactivity was widely distributed into tissues and organs. The apparent volume of distribution of flunisolide in these five species was 3.0-8.0 liters/kg. A major metabolite isolated from rhesus monkey urine was shown to be 6 beta, 11 beta, 16 alpha, 17 alpha, 21-pentahydroxypregna-1,4-diene-3,20-dione 16,17-acetonide (6 beta-OH metabolite). Free 6 beta-OH metabolite was a major radioactive entity detected in urine of all species given radiolabeled flunisolide, whereas flunisolide conjugated with glucuronic acid and/or sulfate was a major metabolite detected in the bile of rats, dogs, and cynomolgus monkeys. Following the oral administration of radiolabeled flunisolide, radioactivity was rapidly and efficiently absorbed in all species, but in the rhesus and cynomolgus monkeys most of the plasma radioactivity was due to the 6 beta-OH metabolite and to water-soluble conjugates, suggesting extensive first-pass metabolism of flunisolide.