Fluticasone furoate/fluticasone propionate – different drugs with different properties

The similarity in the names of the recently introduced intranasal glucocorticoid fluticasone furoate (FF; Veramyst®, GlaxoSmithKline/Avamys®, GlaxoSmithKline UK, Uxbridge, UK) and the earlier fluticasone propionate (FP; Flonase®/Flixonase®, GlaxoSmithKline) has led many to assume that the two compounds have the same active principle (fluticasone) (e.g. 1, 2). This has been compounded by FP commonly, and incorrectly, being abbreviated to fluticasone. The purpose of this letter is to highlight that FF and FP are completely different drugs with FF showing distinct and superior properties (3), and hence prevent any misprescription of these drugs in the future. This confusion clearly stems from the unusual assigned glucocorticoid nomenclature which splits these molecules into the steroidal backbone (fluticasone) and the ester substituent (furoate/propionate). This naming convention does suggest that these derivatives could be ester prodrugs of fluticasone. In fact, a number of topical glucocorticoid esters are indeed ester prodrugs releasing the active parent glucocorticoid in the body. However, fluticasone 17a esters are remarkably stable and remain attached to the fluticasone backbone even during metabolism. Their pharmacological activity is mediated by the entire molecule (backbone + ester) and they share no common metabolites (Fig. 1) – neither FF nor FP is metabolised to fluticasone. FF and FP are therefore structurally distinct drug substances with distinct properties. The furoate and propionate moieties are far from inert appendages but serve to significantly enhance the glucocorticoid activity of fluticasone, which has never itself been developed. Key interactions of FF with the glucocorticoid receptor have been elucidated by X-ray crystallography which shows the ester derived from 2-furoic acid occupying a discrete pocket on the receptor much more completely than does the smaller propionate ester of FP (4). The resulting enhanced affinity of FF for the target receptor is reflected in the lower daily dose of Veramyst (110 mg) compared with Flonase (200 mg). The ester group also contributes to the physicochemical characteristics of the molecule which impact on solubility, dissolution rate, tissue affinity, and hence pharmacokinetic and pharmacodynamic properties. Thus, the ester derived from 2-furoic acid in FF confers higher affinity for both nasal and lung tissue compared Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary. com/onlineopen#OnlineOpen_Terms O OC(O) SCH2F O