title: Comparison of the tissue affinity of glucocorticoids to human lung, nasal and skin tissue in vitro.
abstract: High affinity binding of topically applied glucocorticoids to their target tissues is the basis for prolonged action of the drug and reduces efflux into the systemic circulation that might account for adverse effects. Since little information on the accumulation and depletion of glucocorticoids to tissues of therapeutic interest is available the binding behavior of different glucocorticoids to human lung, nasal and skin tissue is now evaluated and drug concentrations in different tissues are compared. Furthermore, the role of tissue lipids and proteins in glucocorticoid binding is investigated. Therefore, sliced human lung, nasal and skin tissues are incubated with glucocorticoid containing buffers and time course of adsorption and desorption is monitored. Two model glucocorticoids, the highly lipophilic fluticasone propionate (CAS 80474-14-2) and the rather hydrophilic hydrocortisone (CAS 50-23-7) are compared respecting their binding to native and lipid-depleted tissues. While total adsorption rates to different tissues were highly comparable for each glucocorticoid the observed initial desorption was clearly different. Highest initial depletion was seen for lung tissue, lowest for skin tissue. After initial depletion a prolonged desorption of very low concentrations is observed for all tissues. Lipid depletion of tissues did neither change accumulation not depletion behavior except that about twice as high concentrations were bound and depleted, probably due to protein denaturation. It is concluded that glucocorticoids primarily bind to protein components of human lung, nasal and skin tissues. Connective tissue proteins are discussed to bind glucocorticoids with higher affinity than other protein components, thus preventing high initial release rates. While total amounts of adsorption to different tissues are equivalent and initial desorption of glucocorticoids from saturated tissues varies, highest total remaining concentrations should be observed in skin tissue followed by nasal and lung tissue. Although tissue lipids seem to play no role in total glucocorticoid binding they are suggested to influence the rate constant of uptake and depletion.
authors.affiliation: Westfälische Wilhelms-Universität, Institut für Pharmazeutische Chemie, Münster, Germany. hogger@pharmazie.uni-wuerzburg.de
authors.forename: P
authors.initials: P
authors.lastname: Högger
mesh_terms: D000327:Adsorption; D002851:Chromatography, High Pressure Liquid; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D008168:Lung / Q000737:chemistry / Q000378:metabolism*; D009297:Nasal Mucosa / Q000737:chemistry / Q000378:metabolism*; D009584:Nitrogen / Q000032:analysis; D011506:Proteins / Q000378:metabolism; D012867:Skin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D011506:Proteins; D009584:Nitrogen