ABSTRACT:The purpose of this study was to investigate the metabolism and disposition of fluticasone furoate, an enhanced-affinity glucocorticoid receptor agonist, in humans. In a two-part, open-label design study, five healthy male subjects received a p. Fluticasone furoate [(6␣,11␤,16␣,17␣)-6,9-difluoro-17-{[(fluoromethyl)-thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl-2-furancarboxylate] is a new enhanced-affinity glucocorticoid receptor agonist. It is a synthetic fluorinated corticosteroid that has been developed as an intranasal treatment for patients with symptoms of rhinitis. Fluticasone furoate, otherwise known as GW685698X, is not a salt or prodrug because the entire molecule is required for pharmacological activity. It has similar or greater potency than other clinically used corticosteroids (including mometasone furoate, budesonide, fluticasone propionate, and the active principle of ciclesonide) for the glucocorticoid receptor and against the proinflammatory transcription factors nuclear factor B (NF-B), activation protein-1, and tumor necrosis factorinduced interleukin-8 cytokine production (Salter et al., 2007). Agonism of the glucocorticoid receptor is known to suppress the activation of downstream transcription factors, such as NF-B and activation protein-1, and to activate the glucocorticoid response element transactivation pathway (Rhen and Cidlowski, 2005). Inhibition of the NF-B pathway, in particular, is thought to be intimately involved in the anti-inflammatory activity of glucocorticoids because it is a key pathway in the synthesis of a number of inflammatory cytokines (Karin et al., 2004). It is well documented that topical glucocorticoids interact with many of the inflammatory pathways, and there is a large body of clinical evidence to support their use for the treatment of rhinitis, asthma, and chronic obstructive pulmonary disease (Goodman and Gilman, 2006). The purpose of the present study was to investigate the metabolism and disposition of [ 14 C]fluticasone furoate after p.o. and i.v. administration to healthy male subjects. These dose routes were used as surrogates for the intranasal and inhalation routes, from which the majority of the dose is likely to be swallowed. The p.o. route acted as a surrogate for the portion of an intranasal or inhaled dose that is swallowed, and the i.v. route represented the portion absorbed locally into the systemic circulation.

1. Drug-related material was well absorbed following oral administration of 14C-famciclovir to the male rat at doses up to 4000 mg/kg and to the male dog at doses up to 250 mg/kg, as judged by the early onset of the peak blood or plasma concentrations of radioactivity (usually < or = 1.5h) and the rapid extensive excretion of radioactivity in the urine (57-76 and 86-89% of dose in rat and dog respectively). 2. Famciclovir underwent extensive first-pass metabolism in both species. In rat, following dosing at 40 mg/kg, famciclovir was rapidly and extensively metabolized to the active antiviral compound penciclovir, which reached peak concentrations in the plasma (mean 3.5 micrograms/ml) at 0.5 h. The 6-deoxy precursor of penciclovir, BRL 42359, was the only other major metabolite detected in rat plasma. Cmax values for BRL 42359 (mean 2.2 micrograms/ml) were also achieved at 0.5 h. In dog, extensive conversion of famciclovir to penciclovir, via BRL 42359, also occurred, but its rate of formation from BRL 42359 was somewhat slower than in rat. In dog, following dosing at 25 mg/kg, Cmax values for penciclovir (mean 4.4 micrograms/ml) occurred at 3 h and were lower than the Cmax values for BRL 42359 (mean 10.0 micrograms/ml) which were achieved at 1h. 3. A dose-dependent decrease in the conversion of BRL 42359 to penciclovir occurred in both species, resulting a changes in the ratios of the plasma concentrations of the two metabolites with increasing dose. In rat, the urinary excretion of penciclovir decreased from 36% of dose at 40 mg/kg to 21% at 4000 mg/kg, and was accompanied by a corresponding increase in the urinary excretion of BRL 42359. In dog, a similar decrease in the urinary excretion of penciclovir occurred on increasing the dose of famciclovir from 25 to 250 mg/kg. 4. Penciclovir and BRL 42359 were the major metabolites detected in urine and faeces. In rat, following dosing at 40 mg/kg, 54 and 22% of dose were recovered in the excreta as penciclovir and BRL 42359 respectively. Corresponding recoveries of the two metabolites in the dog were 34 and 50% of dose. The metabolic fate of famciclovir in these animal species is, therefore, similar to that reported previously in man.

1. The fate of [14C]BRL 49653C, a novel thiazolidinedione antidiabetic agent, has been studied following oral administration to the rat and dog. 2. Clearance was almost exclusively by metabolism, with only small amounts of unchanged BRL 49653 being excreted by either species. 3. Phase I metabolism resulted in ring hydroxylation, N-demethylation and oxidative removal of the pyridinylamino function to yield a phenoxyacetic acid derivative. 4. Sulphation of phase I metabolites occurred in both species, but glucuronidation was only observed in the rat. 5. The parent compound was the major circulating component in both species at early times, but at later times sulphate conjugates of phase 1 metabolites were predominant.

1. Following oral administration of 14C-famciclovir (500 mg) to three healthy male subjects, drug-related material was rapidly absorbed as judged by peak plasma concentrations of radioactive material being achieved by 0.75 h (6.7 +/- 0.9 microgram equiv./ml (mean +/- SD). 2. Famciclovir underwent extensive first-pass metabolism and was only detected in the plasma of one subject at low concentrations (0.5 microgram/ml). Famciclovir was rapidly and extensively metabolized to the active antiviral compound penciclovir, which reached peak concentrations in the plasma of 3.6 +/- 0.7 microgram/ml (0.75 h). The plasma elimination half-life value for penciclovir was 2.1 +/- 0.1 h. The 6-deoxy precursor of penciclovir, BRL 42359, was the only other relatively major metabolite detected in plasma. Peak plasma concentrations of BRL 42359 (1.0 +/- 0.1 microgram/ml) were achieved at 0.5 h. 3. After 3 days, 73.0 +/- 6.1% of the radioactive dose was excreted in urine, showing that good absorption of drug-related material occurred. Renal excretion was rapid since 60.2 +/- 4.2 and 72.3 +/- 5.7% of the dose was recovered in the urine samples collected up to 6 and 24 h, respectively. A good recovery of the administered radioactive dose was obtained since a further 26.6 +/- 5.1% of the dose was excreted in the faeces over a 72-h period. 4. Penciclovir and BRL 42359 were the major metabolites detected in urine and faeces. Penciclovir accounted for 59.2 +/- 4.9 and 4.2 +/- 1.4% of the dose in 0-24 h urine and 0-48 h faeces, respectively. Corresponding values for BRL 42359 were 5.0 +/- 0.5 and 17.0 +/- 6.2%, respectively. These metabolites were identified in the biological samples using hplc-ms and ms-ms with thermospray ionization.

1. The disposition and metabolic fate of 14C-granisetron, a novel 5-HT3 antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration. 2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species. 3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0.25 and 5 mg/kg in rat and 0.25 and 10 mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man. 4. In rat and dog, 35-41% of the dose was excreted in urine and 52-62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5-25% of dose). 5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.