Correlation of flunisolide plasma levels to eosinopenic response in humans

Abstract

Plasma levels of flunisolide were measured in healthy male volunteers after the administration of single doses of the drug by the intravenous, oral, intranasal, and bronchial inhalation routes. The systemic availability of a 1-mg dose orally was only 21%. After a single dose of approximately 0.117 mg intranasally plasma levels ranged up to 1 ng/ml. When 1 mg was administered by bronchial inhalation, peak or near peak plasma levels were recorded at 2 min and remained near this level throughout the first hour before declining at a rate similar to that observed after flunisolide intravenously (plasma t 1 2 = 1.6 to 2 hr ). Gargling with an alcoholic mouthwash immediately after inhalation reduced plasma levels at 30 and 60 min but not earlier, suggesting rate-limiting dissolution of flunisolide in bronchial fluids or rate-limiting diffusion across the mucociliary blanket or pulmonary membrane. The systemic availabilities of the inhaled-mouthwash and inhaled-no mouthwash doses were 32% and 39%, respectively. Systemic potency of flunisolide, measured by eosinopenic response, was oral < inhaled < intravenous and correlated with the systemic availability of flunisolide after drug administration by these three routes. These pharmacokinetic properties of flunisolide are clinically advantageous in that relatively small doses are delivered topically to the target organs, i.e., the nasal mucosa and lungs, whereas a large portion of the dose is swallowed and subsequently extensively metabolized to relatively inactive metabolites.