Dalman Mechanism of Action

Pharmacotherapeutic group: Corticosteroids. ATC Code: R01AD08.
Pharmacology: Pharmacodynamics: Fluticasone propionate has strong anti-inflammatory activity but does not produce detectable systemic activity when administered topically to the nasal mucosa.
Fluticasone propionate causes little or no hypothalamic-pituitary-adrenal axis suppression following intranasal administration.
Following intranasal dosing of fluticasone propionate, (200 mcg/day) no significant change in 24h serum cortisol AUC was found compared to placebo (ratio 1.01, 90% CI 0.9-1.14).
Pharmacokinetics: Absorption: Following intranasal dosing of fluticasone propionate, (200 mcg/day) steady-state maximum plasma concentrations were not quantifiable in most subjects (<0.01 ng/mL). The highest Cmax observed was 0.017 ng/mL. Direct absorption in the nose is negligible due to the low aqueous solubility with the majority of the dose being eventually swallowed. When administered orally the systemic exposure is <1% due to poor absorption and pre-systemic metabolism. The total systemic absorption arising from both nasal and oral absorption of the swallowed dose is therefore negligible.
Distribution: Fluticasone propionate has a large volume of distribution at steady-state (approximately 318 L). Plasma protein binding is moderately high (91%).
Metabolism: Fluticasone propionate is cleared rapidly from the systemic circulation, principally by hepatic metabolism to an inactive carboxylic acid-metabolite, by the cytochrome P450 enzyme CYP3A4. Swallowed fluticasone propionate is also subject to extensive first pass metabolism. Care should be taken when co-administering potent CYP3A4 inhibitors such as ketoconazole and ritonavir as there is potential for increased systemic exposure to fluticasone propionate.
Elimination: The elimination rate of intravenous administered fluticasone propionate is linear over the 250-1000 mcg dose range and are characterized by a high plasma clearance (CL=1.1 L/min). Peak plasma concentrations are reduced by approximately 98% within 3-4 hours and only low plasma concentrations were associated with the 7.8h terminal half-life. The renal clearance of fluticasone propionate is negligible (<0.2%) and less than 5% as the carboxylic acid metabolite. The major route of elimination is the excretion of fluticasone propionate and its metabolites in the bile.
Toxicology: Preclinical Safety Data: The toxicology appears only in the type of effects that potent corticosteroids have when administered at higher doses than recommended. No new effects were identified in repeated dose toxicity studies, reproductive toxicity studies, or teratology studies.
Fluticasone propionate did not show mutagenic activity in vitro and in vivo and did not show tumorigenic activity in rodents. Not irritating or sensitizing on animal models.