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Systemic Bioavailability of Fluticasone in COPD

I read with interest the article from Sin and colleagues (1), which showed that high dose inhaled fluticasone (500–1,000 µg twice daily) was effective in producing a sustained reduction in serum C-reactive protein (CRP) levels in patients with COPD (mean FEV₁ = 56%). Pointedly, no measurements were made of systemic adverse effects due to inhaled fluticasone. The authors speculated that a direct systemic absorptive effect on fluticasone on CRP would be a less likely explanation owing to its low systemic bioavailability in patients with impaired airway caliber. However, previous data have shown 1,000 µg of fluticasone twice daily for 2 weeks to produce 40% mean suppression of overnight urinary cortisol/creatinine excretion (p = 0.006) and 17% mean suppression of serum osteocalcin (p = 0.03), in patients with severe COPD who have a significant component of emphysema (mean FEV₁ = 43% predicted, DL_CO = 49% predicted) (2). Similar systemic adverse effects with fluticasone were also seen in patients with COPD without significant emphysema (FEV₁ = 51%, DL_CO = 83%), producing 41% and 12% suppression of cortisol and osteocalcin, respectively (2). Thus, it seems quite likely that a significant moiety of inhaled fluticasone was systemically absorbed directly from the lung and subsequently influenced circulating levels of CRP. Although this systemic antiinflammatory effect of high dose inhaled fluticasone may be considered beneficial on cardiovascular outcomes, one has to weigh this against the potential adverse effects on the adrenal gland, bone turnover, blood pressure, glucose, lipids, and other systemic tissues. The trick here will be to establish the relative benefit–risk ratio for the dose–response relationships of inhaled corticosteroids on the suppression of CRP and other systemic adverse effects.

Brian J. Lipworth and Daniel Menzies

Ninewells University Hospital Dundee, UK

FOOTNOTES

Conflict of Interest Statement: B.J.L. and D.M. do not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

1. Sin DD, Lacy P, York E, Man SFP. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170:760–765.[Abstract/Free Full Text]
2. Lee DK, Lipworth BJ. The presence of emphysema does not affect the systemic bioactivity of inhaled fluticasone in severe chronic obstructive pulmonary disease. Br J Clin Pharmacol 2003;57:388–392.

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