Pharmacokinetic/pharmacodynamic evaluation of urinary cortisol suppression after inhalation of fluticasone propionate and mometasone furoate

Br J Clin Pharmacol. 2007 Nov;64(5):698-705. doi: 10.1111/j.1365-2125.2007.02919.x. Epub 2007 May 17.

Abstract

Aim: Fluticasone propionate (FP) and mometasone furoate (MF) are inhaled corticosteroids that possess a high ratio of topical to systemic activity. The systemic bioavailability of MF has been claimed to be minimal (1%). FP has been shown to exhibit the same degree of systemic effects, but its systemic availability is between 13 and 17%. We hypothesize that FP and MF have comparable systemic availabilities that can explain their potential to cause systemic effects.

Methods: Steady-state FP and MF trough plasma samples were determined from a clinical study by Fardon et al. in patients with persistent asthma (forced expiratory volume in 1 s = 91%). The percent plasma protein binding of FP and MF was measured using ultracentrifugation. Free FP plasma concentrations were normalized for their differences in receptor binding affinity compared with MF and linked to overnight urinary cortisol/creatinine with an inhibitory E(max).

Results: A plot of steady-state FP and MF total trough plasma concentrations vs. dose showed that both drugs exhibit dose linearity. MF has comparable bioavailability to FP based on the steady-state concentrations observed for the different doses. The free plasma concentration producing 50% of urinary cortisol suppression (IC(50)) for MF was not statistically different from the free, normalized IC(50) for FP.

Conclusion: FP and MF have similar pulmonary deposition and the same potential to cause systemic side-effects due to their similar IC(50) values. The observed urinary cortisol suppression of FP and MF is in agreement with their systemic availability, their differences in plasma protein binding and receptor binding affinity.

MeSH terms

  • Administration, Inhalation
  • Adult
  • Aged
  • Androstadienes / administration & dosage
  • Androstadienes / metabolism
  • Androstadienes / pharmacokinetics*
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / pharmacokinetics*
  • Female
  • Fluticasone
  • Humans
  • Hydrocortisone / urine*
  • Male
  • Middle Aged
  • Mometasone Furoate
  • Pregnadienediols / administration & dosage
  • Pregnadienediols / metabolism
  • Pregnadienediols / pharmacokinetics*
  • Protein Binding / drug effects
  • Treatment Outcome

Substances

  • Androstadienes
  • Anti-Inflammatory Agents
  • Pregnadienediols
  • Mometasone Furoate
  • Fluticasone
  • Hydrocortisone