A review of the pharmacology and pharmacokinetics of inhaled fluticasone propionate and mometasone furoate.

BACKGROUND: Fluticasone propionate is an established corticosteroid administered intranasally for the treatment of rhinitis or by oral inhalation for the treatment of asthma. Mometasone furoate, a closely related corticosteroid currently available in an intranasal formulation, is being investigated in an oral inhalation formulation for the treatment of asthma. OBJECTIVE: This article reviews available data on the comparative structure-activity relationships, chemistry, pharmacology, pharmacokinetics, and systemic bioavailability of fluticasone propionate and mometasone furoate to assess whether claims of differences in the absolute systemic bioavailability of the 2 compounds are supported by the published literature. METHODS: Information for this review was identified through a MEDLINE search of the literature from 1966 to the present that contained the term mometasone or fluticasone. The resulting list was narrowed by excluding articles dealing with dermatologic applications. A systematic review was conducted of the identified literature pertaining to the molecular structure, topical potency, lipophilicity, pharmacokinetics, and bioavailability of the 2 agents. Additionally, the pharmacology of the 2 moieties was assessed by a review of the available literature on receptor binding affinity, transactivation and transrepression potency, and inhibition of inflammatory-cell cytokine expression. RESULTS: Based on the available data, fluticasone propionate and mometasone furoate have similar physicochemical properties and structure-activity relationships. When administered intranasally, mometasone furoate is reported to have comparable relative systemic bioavailability to that of fluticasone propionate (mean plasma area under the curve, 123 pmol x h/L vs 112 pmol x h/L, respectively). When administered as a single dose by dry powder inhaler, orally inhaled fluticasone propionate is reported to have a total systemic bioavailability of approximately 17%, whereas that of mometasone furoate is reported to be < 1%. However, the mometasone furoate bioavailability study that reported the latter value used lower drug doses and a less sensitive assay than the fluticasone propionate bioavailability study. When multiple-dose data were used, mometasone furoate had an estimated 11% systemic bioavailability, similar to that of fluticasone propionate. CONCLUSIONS: Inhaled fluticasone propionate and mometasone furoate appear to have comparable potential systemic absorption and, based on the total systemic bioavailabilities of the parent compounds, have a low potential for systemic side effects at the recommended clinical doses. However, in the case of mometasone furoate, the contribution of the active metabolites to systemic effects has not been adequately assessed.

Blockade and reversal of endothelin-induced constriction in pial arteries from human brain.

BACKGROUND AND PURPOSE: Substantial evidence now implicates endothelin (ET) in the pathophysiology of cerebrovascular disorders such as the delayed vasospasm associated with subarachnoid hemorrhage and ischemic stroke. We investigated the ET receptor subtypes mediating vasoconstriction in human pial arteries. METHODS: ET receptors on human pial and intracerebral arteries were visualized with the use of autoradiography, and the subtypes mediating vasoconstriction were identified by means of wire myography. RESULTS: ET-1 was more potent than ET-3 as a vasoconstrictor, indicating an ETA-mediated effect. Similarly, the selective ETB agonist sarafotoxin S6c had no effect on contractile action at concentrations up to 30 nmol/L. The nonpeptide ETA receptor antagonist PD156707 (3 to 30 nmol/L) caused a parallel rightward shift of the ET-1-induced response, yielding a pA2 of 9.2. Consistent with these results, PD156707 (30 nmol/L) fully reversed an established constriction in pial arteries induced by 1 nmol/L ET-1, while the selective ETB receptor antagonist BQ788 (1 micromol/L) had little effect. The calcium channel blocker nimodipine (0.3 to 3 micromol/L) significantly attenuated the maximum response to ET-1 in a concentration-dependent manner without changing potency. In agreement with the functional data, specific binding of [125I]PD151242 to ETA receptors was localized to the smooth muscle layer of pial and intracerebral blood vessels. In contrast, little or no [125I]BQ3020 binding to ETB receptors was detected. CONCLUSIONS: These data indicate an important role for ETA receptors in ET-1-induced constriction of human pial arteries and suggest that ETA receptor antagonists may provide additional dilatory benefit in cerebrovascular disorders associated with raised ET levels.

Endothelin receptor subtypes and their functional relevance in human small coronary arteries.

1. The potent constrictor peptide endothelin (ET) has been implicated in various cardiovascular disorders including myocardial infarction and atherosclerosis. We have investigated the nature of ET receptor subtypes present on human small coronary arteries. 2. Small coronary arteries were mounted in a wire-myograph for in vitro pharmacology. To investigate the ET receptor subtypes present in different segments of the coronary vascular tree, arteries were grouped according to internal diameter. Responses in arteries with small internal diameters (mean 316.7+/-7.9 microm; Group B) were compared to those in larger arteries (mean 586.2+/-23.1 microm; Group A). 3. ET-1 consistently and potently contracted arteries from Group A and B, with EC50 values of 1.7 (0.9-3.2) nM (n=15) and 2.3 (1.4-4.2) nM (n=14), respectively. No correlation was observed between ET-1 potency and internal diameter. The response to ET-1 was potently antagonized by the selective ET(A) receptor antagonist PD156707 in both Group A and Group B, yielding pA2 values of 8.60+/-0.12 (n=4-6) and 8.38+/-0.17 (n=4-6), respectively. Slopes from Schild regression were not significantly different from unity. 4. In contrast to ET-1, individual responses to ET-3 were variable. While all arteries from Group A responded to ET-3 (EC50 approximately 69 (23-210) nM) (n=12), no response was obtained in 5 of the 14 tested in Group B. Of those responding, many failed to reach a maximum at concentrations up to 1 microM. ET-1 was more potent than ET-3 in all arteries tested. A biphasic ET-3 response was observed in 8 arteries suggesting that a small ET(B) population was also present in some patients. The selective ET(B) receptor agonist sarafotoxin S6c had little or no effect up to 10 nM (n=4-6). 5. Responses to ET-1 and ET-3 were unaffected by removal of the endothelium in arteries from both groups suggesting a lack of functional, relaxant ET(B) receptors on endothelial cells (n=5). 6. Using autoradiography, specific high density binding of the non-selective, ET(A)/ET(B) ligand [125I]-ET-1 and selective ET(A) ligand [125I]-PD151242 was detected on the vascular smooth muscle layer of small intramyocardial coronary arteries (n=5). In contrast, little or no binding of the selective ET(B) receptor ligand [125I]-BQ3020 was observed (n=5). Similarly, [125I]-ET-1 binding to vascular smooth muscle was absent in the presence of the selective ET(A) receptor antagonist PD156707. 7. We conclude that human small epi- and intramyocardial coronary arteries express predominantly ET(A) receptors and it is these receptors which mediate ET-induced contractions. A constrictor ET(B) receptor population may exist in some patients. However, these receptors may have a limited role as contractions to ET-1 can be blocked fully by the selective ET(A) receptor antagonist PD156707.

Relative contribution of endothelin A and endothelin B receptors to vasoconstriction in small arteries from human heart and brain.

Endothelin (ET) has been implicated in cardiovascular disorders such as stroke and myocardial ischemia. Given the important role of the resistance vasculature in the control of blood flow, we investigated the ET receptors that mediate vasoconstriction in human small pial and coronary arteries supplying the brain and heart, respectively. ETA receptors were localized by autoradiography to the vascular smooth-muscle layer of pial, intracerebral, and intramyocardial arteries. In contrast, little ETB binding was observed. ET-1 was a more potent constrictor than ET-3 in both pial and coronary arteries. Biphasic ET-3 responses were obtained in four of 15 coronary arteries tested. The ETB agonist sarafotoxin S6c had little or no effect in these vessels. The nonpeptide, selective ETA receptor antagonist PD156707 caused a parallel shift to the right of the concentration-response curve to ET-1, yielding pA2 values of 9.17 +/- 0.07 and 8.38 +/- 0.17 in pial and coronary arteries, respectively. Slopes from Schild analysis were not significantly different from unity. These data suggest that ETA receptors predominate on the smooth-muscle layer of human small pial arteries. Coronary arteries also express mainly ETA receptors. However, a small population of contractile ETB receptors may also be present in some patients.

Autoradiographic study of endothelin receptors in human cerebral arteries.

Endothelin (ET) has recently been implicated in the pathogenesis of a variety of cerebrovascular disorders. In particular, it has been linked to the delayed cerebral vasospasm associated with subarachnoid hemorrhage (SAH). In the present study we have identified the ET receptors present on human middle meningeal and pial arteries. Qualitative autoradiography was carried out using [125I]ET-1 to visualize the total ET receptor population or [125I]PD151242, or [125I]BQ3020, ETA- and ETB-selective receptor ligands, respectively. [125I]ET-1 and [125I]PD151242 bound specifically with high density to the vascular smooth muscle of both arteries; little or no specific [125I]BQ3020 binding was detected. Immunocytochemistry localized the mature ET to endothelial cells of pial arteries. These results show that ETA receptors predominate in human middle meningeal and pial arteries. In pial arteries, ET, which may be synthesized locally by the endothelium, may then act on this receptor subtype. However, it has yet to be determined whether this receptor subtype is involved in conditions such as the delayed vasospasm associated with SAH. The possibility of changes in ET receptor subtype(s) under pathophysiologic conditions should be considered.