Pharmacological properties of the enhanced-affinity glucocorticoid fluticasone
furoate in vitro and in an in vivo model of respiratory inflammatory disease
Mark Salter,1Keith Biggadike,2Joyce L. Matthews,2Michael R. West,2Michael V. Haase,2
Stuart N. Farrow,2Iain J. Uings,2and David W. Gray3
1Global Project Management, GlaxoSmithKline, Ware;2Respiratory and Inflammation Centre for Excellence in Drug
Discovery, GlaxoSmithKline, Stevenage; and3Discovery Research, GlaxoSmithKline, Harlow, UK
Submitted 20 March 2007; accepted in final form 12 June 2007
Salter M, Biggadike K, Matthews JL, West MR, Haase MV,
Farrow SN, Uings IJ, Gray DW. Pharmacological properties of the
enhanced-affinity glucocorticoid fluticasone furoate in vitro and in an
in vivo model of respiratory inflammatory disease. Am J Physiol Lung
Cell Mol Physiol 293: L660–L667, 2007. First published June 15,
2007; doi:10.1152/ajplung.00108.2007.—Fluticasone furoate (FF) is
a novel enhanced-affinity glucocorticoid that has been developed as
topical therapy for allergic rhinitis. The pharmacological properties of
FF have been investigated using a number of in vitro experimental
systems. FF demonstrated very potent glucocorticoid activity in sev-
eral key pathways downstream of the glucocorticoid receptor (GR) as
follows: the transrepression nuclear factor-?B (NF-?B) pathway, the
transactivation glucocorticoid response element pathway, and inhibi-
tion of the proinflammatory cytokine tumor necrosis factor-?. Fur-
thermore, FF showed the greatest potency compared with other
glucocorticoids for preserving epithelial integrity and reducing epi-
thelial permeability in response to protease- and mechanical-induced
cell damage. FF showed a 30- to ?330,000-fold selectivity for
GR-mediated inhibition of NF-?B vs. the other steroid hormone
receptors, substantially better than a number of other clinically used
glucocorticoids. In studies examining the respiratory tissue binding
properties of glucocorticoids, FF had the largest cellular accumulation
and slowest rate of efflux compared with other clinically used glu-
cocorticoids, consistent with greater tissue retention. The in vivo
anti-inflammatory activity of FF was assessed in the Brown Norway
rat ovalbumin-induced lung eosinophilial model of allergic lung
inflammation. At a dose of only 30 ?g, FF achieved almost total
inhibition of eosinophil influx in the lung, an inhibition that was
greater than that seen with the same dose of fluticasone propionate. In
conclusion, the potent and selective pharmacological profile of FF
described here could deliver an effective, safe, and sustained topical
treatment of respiratory inflammatory diseases such as allergic rhinitis
anti-inflammatory; tissue retention; allergic rhinitis; nasal; once daily
GLUCOCORTICOIDS ARE COMMONLY used to treat a wide range of
inflammatory conditions such as asthma, allergic rhinitis,
chronic obstructive pulmonary disease, rheumatoid arthritis,
inflammatory bowel disease, and autoimmune diseases (15).
Despite advances in the compounds and formulations em-
ployed in clinical practice, there are limitations to currently
available glucocorticoids. In particular, among the intranasal
glucocorticoids used in the treatment of allergic rhinitis, in-
complete symptom reduction, the need for twice-daily dosing,
and unpleasant sensory attributes all contribute to suboptimal
management of the disease. Therefore, there remains an unmet
clinical need for intranasal glucocorticoids with enhanced
symptom reduction, a longer duration of action, and improved
Glucocorticoids mediate their effects on the body through
the glucocorticoid receptor (GR). Activated GR affects a num-
ber of downstream pathways via DNA-binding-dependent
(e.g., transactivation) and -independent (e.g., transrepression)
mechanisms. DNA-binding-dependent effects are mediated via
binding of the activated GR directly to DNA at specific
recognition sites, known as glucocorticoid response elements
(GREs), to effect either an increase or decrease in the tran-
scription of certain gene products. Glucocorticoid-activated
GR can also interact directly with certain transcription factors,
such as the proinflammatory nuclear factor-?B (NF-?B; with-
out binding directly to DNA), and consequently inhibit their
ability to increase the transcription of a variety of proinflam-
matory gene products (2).
Fluticasone furoate (FF, GW685698X; see Ref. 20) is a
novel enhanced-affinity glucocorticoid with a unique combi-
nation of pharmacodynamic and physicochemical properties.
FF was identified following a detailed investigation of the
effect of modification of the 17?-ester moiety of the glucocor-
ticoid fluticasone propionate (FP). Although FF is structurally
related to FP, they are distinct chemical and pharmacological
entities (Fig. 1).
Some glucocorticoids, such as beclomethasone dipropionate
and ciclesonide, require de-esterification [to beclomethasone
17-monopropionate and des-isobutyryl-ciclesonide (active
principle, Cic-AP), respectively] for pharmacological activity.
Neither FF nor FP require de-esterification for activity; in both
cases, the activity resides in the entire molecule. Both FF and
FP have a fluoromethylthioester at the 17?-position that is
cleaved during hepatic metabolism to inactivate any gluco-
corticoid that enters the systemic circulation. However, the
17?-ester group of FF and FP (furoate and propionate, respec-
tively) is metabolically stable and is not cleaved from the rest
of the molecule. FF and FP share no common metabolites, and
neither compound is metabolized to fluticasone (Fig. 1). FF is
therefore a distinct drug molecule and not a salt or a prodrug of
For optimal efficacy and minimal side effects, topical glu-
cocorticoids should display high local efficacy with low sys-
temic exposure and adverse effects. Previous studies have
shown that FF binds with a greater affinity to the human GR
than other clinically used glucocorticoids (22). The current
Address for reprint requests and other correspondence: M. Salter, Global
Project Management, Bldg. 1, GlaxoSmithKline, Park Rd., Ware SG12 0DP,
UK (e-mail: firstname.lastname@example.org).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
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Am J Physiol Lung Cell Mol Physiol 293: L660–L667, 2007.
First published June 15, 2007; doi:10.1152/ajplung.00108.2007.
1040-0605/07 $8.00 Copyright © 2007 the American Physiological Society http://www.ajplung.orgL660
Norway rat model shows a characteristic eosinophil inflamma-
tion of the lung, elicited by an allergic response to the admin-
istration of ovalbumin. Glucocorticoids that have been shown
to be effective in rhinitis and inflammatory respiratory disease
are also effective inhibitors of this eosinophilia (7, 23). In this
model, FF demonstrated a more potent suppression of inflam-
mation than that seen with FP, confirming the results of the
in vitro studies.
In conclusion, this paper suggests that the combination of
the fluticasone backbone and 17?-furoate ester in FF provides
the optimal combination for potency, tissue binding, and ste-
roid hormone selectivity. The enhanced affinity of GR binding
of FF, coupled with its extended tissue association, could be
expected to lead to greater and more prolonged anti-inflamma-
tory effects compared with other clinically used glucocorti-
coids and should provide true once-daily efficacy. In addition,
the high selectivity of FF for GR, coupled with its avid target
tissue retention, rapid systemic clearance, and high plasma
protein binding, should provide a safe clinical profile. FF is
currently under investigation for the treatment of allergic
rhinitis. The results of these studies will help establish the
effectiveness of this novel enhanced-affinity glucocortiocoid in
a clinical setting.
We thank Rob Austin, Margaret Clackers, and Yemisi Solanke for technical
assistance with various in vitro assays, Mike Davies and Dr. Mark Lennon for
help with the statistical analysis, and Drs. John Dunlop and Anna Koundouris
for writing assistance and manuscript management.
The studies included in this manuscript were funded by GlaxoSmithKline,
and all authors are employees of GlaxoSmithKline.
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PHARMACOLOGICAL STUDY OF FLUTICASONE FUROATE
AJP-Lung Cell Mol Physiol • VOL 293 • SEPTEMBER 2007 • www.ajplung.org