Absolute oral versus inhaled bioavailability: significance for inhaled drugs with special reference to inhaled glucocorticoids.

Abstract

Orally inhaled drugs provide great benefit in the treatment of asthma as they are delivered directly to the site of action, i.e. the lung. The absolute oral inhaled bioavailability of a glucocorticoid results from the combination of the bioavailability of the dose delivered to the lung and the bioavailability of the dose delivered into the gastrointestinal (GI) tract. The majority of the dose delivered to the lung is absorbed and available systemically. For the portion of the glucocorticoid dose delivered orally, bioavailability depends upon absorption from the GI tract and the extent of first pass/pre-systemic metabolism in the GI tissue and liver. Since this oral component of the delivered dose does not provide any beneficial therapeutic effect but can contribute to the systemic side effects, it is desirable for the absolute oral bioavailability of inhaled glucocorticoids to be relatively low (which is the case with most of the glucocorticoids, < 25%). Another approach to limiting systemic exposure from inhaled delivery is to improve the effectiveness of the oral inhaled formulation and delivery device, by increasing the fraction of the total inhaled dose which reaches the lung. Since current inhalation technology can provide respirable fractions in the range of 30-50%, what is the significance of the oral component of systemic exposure in relation to the overall systemic exposure following the oral inhalation administration of glucocorticoids? Below a certain point (approximately 25%), lower oral bioavailability of inhaled drugs may not be clinically important with respect to systemic exposure if the lung targeting is good (30%).