Metabolism and Disposition of Fluticasone Furoate, an Enhanced-Affinity Glucocorticoid, in Humans

Abstract

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.

Metabolism of Beclomethasone Dipropionate by Cytochrome P450 3A Enzymes

“…This mass shift and corresponding 16-amu shifts in several diagnostic fragment ions of BDP, most notably m/z 409, 427, and 445, which corresponded to the neutral loss of the D-ring substituents on C-17 and C-21, loss of water, and HCl, indicated hydroxylation of the core structure of BDP. The fragmentation pattern for [M4] excluded oxygenation on the propionate groups, suggesting that [M4] was most likely 6b-OH-BDP based on the fact that steroids and structurally similar glucocorticoids preferentially undergo 6b-hydroxylation by CYP3A enzymes and [M4] was a common metabolite for both CY3A4 and 3A7 (Jonsson et al, 1995;Teng et al, 2003;Peet et al, 2005;Pearce et al, 2006;Hughes et al, 2008).…”

Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes

“…However, more recent work using fluticasone furoate has detected defluorinated and several hydroxylated metabolites in plasma and fecal samples (Hughes et al, 2008). Therefore, it was concluded that fluticasone propionate was metabolized by oxidative defluorination and hydroxylation by CYP3A enzymes.…”

Phamacology of fluticasone furoate and vilanterol trifenatate combination therapy for asthma

“…The time for 90% absorption from the lung was significantly longer for FF (20-30 h) than for FP (8 h), indicating a significantly longer lung retention time for FF [15]. Therefore, systemic exposure to FF following inhalation results predominantly from absorption across the lung, while systemic exposure from the swallowed portion is metabolized by extensive first-pass hepatic metabolism resulting in a negligible gastrointestinal bioavailability [16]. Similarly, BUD has a high therapeutic ratio, with, high local potency at the site of application but relatively low systemic potency after absorption.…”

“…Oral and intravenous administration of [14C]-FF to healthy male subjects was characterized by high plasma clearance (58.3 L/h) and a very large volume of distribution (642 L) indicating extensive tissue uptake [16]. After intravenous administration of the drug, which acted as a surrogate for the component of drug absorbed locally into the systemic circulation, there was a moderate plasma half-life of 15.3 h [16].…”