Received for publication May 1, 2008.
Revised August 7, 2008.
Accepted for publication August 7, 2008.

Metabolism and disposition of fluticasone furoate, an enhanced-affinity glucocorticoid, in humans

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 an oral dose of 2 mg [¹⁴C] fluticasone furoate, followed 4 weeks later by an intravenous dose of 0.25 mg [¹⁴C] fluticasone furoate (as a 30 min infusion). Oral absorption was rapid and estimated at approximately 30%, although the oral bioavailability was markedly lower at 1.6%, limited by extensive first-pass metabolism. Plasma clearance (CLp) was 58.3 L/h, with a volume of distribution (Vss) of 642 L and a terminal elimination half-life of 15.3 h. The major circulating component identified in plasma extracts after intravenous and oral dosing was unchanged parent compound, with GW694301X (M10) also being notable after oral administration. Mean recovery of radioactivity was approximately 92% and 102% at 216 and 168 h after intravenous and oral administration, respectively, with most (at least 90%) recovered in the faeces. Fluticasone furoate was extensively metabolised, with only trace amounts of unchanged parent compound observed in faeces following either route of administration. The predominant pathway was removal of the S-fluoromethyl carbothioate group, to yield the 17 carboxylic acid (GW694301X, M10). Other pathways included oxidative defluorination to yield a hydroxyl at the C6 position. There was no evidence for metabolic loss of the furoate group from fluticasone furoate or any of its metabolites. Evidence presented suggests that enterocytes have a role in the metabolism of unabsorbed fluticasone furoate.

Key words: absorption, clinical pharmacokinetics, drug absorption, drug clearance, drug distribution, excretion, HPLC, human pharmacokinetics, mass spectrometry, pharmacokinetics