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Side Effects With Inhaled Corticosteroids: Systemic Side Effects With ICS Therapy Systemic Availability of ICS

Published in Asthma

ICS absorption into the systemic circulation occurs either through the lungs or by swallowing drug that is not inhaled but deposited at the back of the throat. Nevertheless, other factors need to be considered and these are discussed below.
The contribution of GI absorption to systemic ICS exposure is minimal compared with that of absorption through the lungs. ICS that are swallowed and absorbed in the gut will undergo hepatic first-pass metabolism, greatly reducing the amount of circulating drug. The degree of hepatic first-pass metabolism differs between ICS: FP and MF, 99%; BUD, 90%; TAA, 80 to 90%; and BDP, 60 to 70%. Theoretically, agents that are inactivated by hepatic first-pass metabolism should be safer. However, highly lipophilic drugs, such as FP and MF, will be taken up more readily into tissues than drugs that are less lipophilic, such as TAA and BUD.

Because more extensive tissue storage of ICS in an active form will result in a longer clearance time from the body, this not only may increase the duration of therapeutic effect but it also may increase the potential for increased systemic side effects should active drug continue to be released back into the circulation. There is another potential reason why there is an increased risk of systemic side effects with MF. In contrast to other ICS, MF generates an active metabolite (6^-OH MF) in the liver and an active degradation product (9,11-epoxy MF) in the lung and plasma. Even though MF itself has a low systemic bioavailability, these active metabolites will contribute to the overall potential for MF therapy to cause systemic side effects. It has been shown that MF does cause significant overnight urinary cortisol suppression, a marker for hypothalamic-pituitary-adrenal axis suppression, to a similar extent as FP.

Most systemic ICS originates from direct absorption into the circulation through lower airway deposition. This route avoids hepatic first-pass metabolism. Drugs that are highly protein bound in the circulation will have a low potential for causing systemic side effects because only the free fraction is biologically active. The degree of protein binding is 71% for TAA, 80% for flunisolide (FLU), 88% for BUD, 90% for FP, and > 99% for ciclesonide (CIC).> Protein binding for BDP is 87%, but no data are available for its active metabolite, 17 be-clomethasone monopropionate.
Factors that increase ICS airway delivery may improve efficacy but may also increase the risk of systemic side effects. For example, patients with mild disease have less airway obstruction than patients with more severe disease, increasing the deposition of ICS into the lower airways, possibly increasing the risk of side effects for the same ICS dose. For example, administration of inhaled FP (1,000 ^g) to normal, healthy subjects resulted in higher peak plasma concentrations and greater total drug systemic exposure than for asthma patients. Systemic availability of FP was also lower in asthma patients than in healthy control subjects, with a mild correlation to lung function as measured by FEVj (r = 0.47, p = 0.02).