Comparison of Inhaled Corticosteroids: An Update

H William Kelly, PharmD


The Annals of Pharmacotherapy. 2009;43(3):519-527. 

In This Article

Pharmacokinetic Differences

The pharmacokinetic differences for inhaled corticosteroids are what determine their relative topical to systemic effect ratio or therapeutic index. Factors that enhance the therapeutic index are decreased oral absorption, retention in the lung, and rapid systemic clearance once the drug is absorbed into the systemic circulation.[9,10,11,12,13,14] More recently, it has been posited that high plasma protein binding would also enhance the therapeutic index.[2,13,14] Pharmacokinetic differences between the inhaled corticosteroids are listed in Table 2. Because the first CFC-MDI preparations delivered the majority (70–80%) of the drug into the oropharynx, which was then swallowed, decreasing oral bioavailability by either decreased absorption or first-pass metabolism by the gut lining or the liver significantly enhanced the therapeutic index of the first inhaled corticosteroids (beclomethasone dipropionate, flunisolide, triamcinolone acetonide) over the dexamethasone MDI, which was 100% orally available.[9] Then, budesonide and fluticasone propionate had reduced oral bioavailability that further enhanced their therapeutic indexes, although the difference between beclomethasone dipropionate and budesonide could be overcome with the use of a spacer device that reduced oropharyngeal deposition.[9,22,33] The 2 newest inhaled corticosteroids (mometasone furoate and ciclesonide) have very low oral bioavailability, similar to that of fluticasone propionate (Table 2).[2,7]

Retention of an inhaled corticosteroid in the lung following inhalation can be accomplished by distribution into the lipophilic tissues of the lung and slow absorption into the systemic circulation, resulting in more prolonged apparent elimination half-life following inhaled administration versus intravenous administration.[9,11] Another possible mechanism for prolonging retention in the lung is intracellular fatty acid esterification with inhaled corticosteroids that have a free hydroxyl group at the carbon 21 position (ie, budesonide, triamcinolone acetonide, des-ciclesonide).[11,14] Although fatty acid esterification can be shown both in vitro and in vivo, this property has not been established to confer an improved therapeutic index or prolonged duration of effect over agents that do not undergo esterification.[11,14,52]

It has been hypothesized that high plasma protein binding would diminish tissue distribution, thus enhancing the therapeutic index of inhaled corticosteroids; however, available data do not support this hypothesis.[5,7,8] Mometasone furoate, 1 of the 2 inhaled corticosteroids with the highest protein-binding (Table 2), has not demonstrated an improved therapeutic index over fluticasone propionate, which shares the same pharmacokinetic profile.[7,53] In addition, the relatively low affinity binding to serum albumin is not restrictive in that the distribution volume and systemic clearance of both mometasone furoate and des-ciclesonide are high.[2,7]

Systemic clearance and bioavailability are the primary determinants of systemic exposure of a drug. All of the currently available inhaled corticosteroids undergo extensive metabolic conversion in the liver, primarily by the CYP3A4 enzyme subfamily, with unrestrictive hepatic extraction.[11,14] Systemic clearance of inhaled corticosteroids is primarily limited by hepatic blood flow (~90 L/h). However, des-ciclesonide and beclomethasone monopropionate have clearance exceeding hepatic blood flow, reflecting extrahepatic elimination, possibly via blood esterase activity.[2,54] The high oral availability of beclomethasone monopropionate (~40%) counteracts the effect of higher clearance on therapeutic index. However, the 2-fold greater clearance of des-ciclesonide, with its concomitant low oral availability, should provide an enhanced therapeutic index. Current data are inconclusive, as studies seldom have used dose-ranging or equivalent doses.[3,4] One dose-ranging trial noted that 1760 µg/day of fluticasone propionate CFC-MDI produced a significant reduction in 24-hour UFC compared with placebo and that the value for 1280 µg/day of ciclesonide was between that seen for 880 µg/day and 1760 µg/day of fluticasone propionate, as one would predict based on potency and delivery differences.[51] Thus, further studies are needed to assess the therapeutic index of ciclesonide relative to that of other inhaled corticosteroids.


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