The human pharmacology of fluticasone propionate

Fluticasone propionate is a potent, locally active glucocorticoid which has no demonstrable systemic side-effects when given by the oral or intranasal routes. The recommended clinical dose for rhinitis is 200 micrograms once a day intranasally or twice a day if symptoms persist. Four studies are described which establish the metabolic and pharmacokinetic features of fluticasone propionate and which assess the systemic effects of oral and intranasal doses in healthy volunteers. The drug was cleared rapidly by metabolism, with a total blood clearance equivalent to hepatic blood flow. On this basis, the expected extraction ratio would approach unity and oral systemic bioavailability would approach zero. This was confirmed by the absence of unchanged drug in the plasma up to 6 h after dosing with 1 mg or 16 mg of drug. The principal metabolite found, the 17-carboxylic acid derivative, has negligible glucocorticoid activity. This rapid clearance to an inactive metabolite is the basis for the observed lack of effects on the hypothalamo-pituitary-adrenal axis after single, night-time doses of fluticasone propionate, 16 mg orally, and after fluticasone propionate, 4 mg intranasally for 1 week. The virtually zero oral bioavailability and lack of systemic effects by the oral and intranasal routes are features which are unique compared with other glucocorticoids used clinically.