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Pharmacology: Pharmacodynamics: Fluticasone propionate is a potent corticosteroid with high affinity to the glucocorticoid receptors and used for the treatment of allergic rhinitis. It has potent topical anti-inflammatory effect and weak systemic activity.
In a trial to evaluate the potential systemic and topical effects of nasal spray on allergic rhinitis symptoms, the benefits of comparable drug blood levels produced by nasal spray and oral fluticasone propionate were compared. The doses used were 200 mcg of nasal spray, the nasal spray vehicle (plus oral placebo) and 5 and 10 mg of oral fluticasone propionate (plus nasal spray vehicle) per day for 14 days. Plasma levels were undetectable in the majority of patients after intranasal dosing, but present at low levels in the majority after oral dosing. Nasal spray was significantly more effective in reducing symptoms of allergic rhinitis. This trial demonstrated that the therapeutic effect of nasal spray is attributed to the topical effect of fluticasone propionate.
Fluticasone propionate has no effect on the hypothalamic-pituitary-adrenal (HPA) axis. When fluticasone propionate is applied on intranasal mucosa, a part of the drug is absorbed by nasal mucosa then transferred to systemic circulation and the remainder is eliminated by the nasal mucosal activation and by swallowing.
Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediators (e.g. histamine, eicosanoids, leukotrienes, and cytokines). Corticosteroids do not have sudden effect on allergic symptoms.
Pharmacokinetics: Absorption: After intranasal application, fluticasone propionate has an absolute bioavailability averaging less than 2%. After intranasal treatment of patients with allergic rhinitis for 3 weeks, fluticasone propionate plasma concentrations were above the level of detection (50 ρg/ml). Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Studies using oral dosing of radiolabeled drug have demonstrated that fluticasone propionate highly extracted from plasma and absorption is low. Oral bioavailability is negligible and the majority of the circulating radioactivity is due to an inactive metabolite.
Distribution: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 l/kg. The percentage of fluticasone propionate bound to human plasma proteins averaged 91 % with no obvious concentration relationship. Fluticasone propionate is weakly and reversibly bound to erythrocytes and freely equilibrates between erythrocytes and plasma. Fluticasone propionate is not significantly bound to human transcortin.
Metabolism: The total blood clearance of fluticasone propionate is high (average, 1.093 ml/min), with renal clearance less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This inactive metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacologic activity in studies.
Elimination: Following intravenous dosing, fluticasone propionate showed a terminal elimination half-life of 7-8 hours. Less than 5% of the dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.
