Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects

Abstract

Aims The present study was undertaken to see whether the difference in plasma cortisol suppression between single and repeated dosing of fluticasone propionate (FP) can be explained by systemic accumulation. Methods Twelve healthy subjects (six women) were given, in a crossover fashion, a single dose inhalation (1000 mg ) of FP via DiskhalerA and repeated inhalations (1000 mg twice daily) every 12 h during 7 days. There was a washout period of 2 weeks between the treatments. An intravenous dose of 20 mg FP was given as a reference. Plasma concentrations of FP for each treatment were determined by liquid chromatography plus tandem mass spectrometry. Plasma cortisol after the inhaled doses was determined using an immunoassay and was compared with baseline values. Results The average plasma concentration of FP was about 1.7 times higher after multiple inhalations than after a single dose. Systemic availability, mainly attributable to pulmonary deposition, was 15.6 [13.6-18.0]% of the nominal dose. Daytime plasma cortisol suppression vs baseline was 47 [20-65]% and 95 [93-97]% for the single and repeated doses, respectively. Conclusions To conclude, a slow elimination of FP leads to accumulation during repeated dosing. This accumulation may explain the marked decrease in plasma cortisol seen during treatment with fluticasone propionate within the clinical dose range.

Differences in Endogenous Esterification and Retention in the Rat Trachea between Budesonide and Ciclesonide Active Metabolite

“…High lipophilicity increases both the GC uptake and retention in airway tissue (i.e., decelerates removal of GCs from airway tissue), and thereby enhances and prolongs anti-inflammatory efficacy of inhaled GCs in the airways (Brattsand, 1997). On the other hand, high lipophilicity can be a disadvantage in the peripheral tissues leading to enhanced distribution and retention, prolonged terminal plasma halflife, and accumulation (Thorsson et al, 1997(Thorsson et al, , 2001Lipworth and Jackson, 2000). Furthermore, highly lipophilic inhaled GCs have a low water solubility which may increase the GC fraction that is cleared by mucocilliary escalator before it is dissolved in airway fluid and absorbed into airway tissue and becomes available for cytosolic GC receptor (Edsbäcker, 2002).…”

Adrenal suppression from high-dose inhaled fluticasone propionate in children with asthma: Fig. 1.—

“…Paediatric studies suggest that FP in doses of f400 mg?day -1 does not produce significant systemic adverse effects [4,[11][12][13].…”

“…After repeated doses, FP demonstrates a moderate degree of accumulation [8,9]. It has been suggested that such accumulation may play a more important role in HPA axis suppression than peak plasma concentrations [10,11].…”

Comparative lung bioavailability of fluticasone/salmeterol via a breath-actuated spacer and conventional plastic spacers

“…FP has negligible oral bioavailability on account of its near complete hepatic first pass metabolism [8,9]. Therefore the systemic bioavailability of FP is dependant entirely on lung absorption and therefore the delivered lung dose.…”