Brain permeability of inhaled corticosteroids

• DOI: 10.1211/jpp.57.9.0010
• Publication Date: 2005-08-04T22:50:15Z
• Authors: Vikram Arya; Manish Issar; Yaning Wang; Guenther Hochhaus; James D Talton
• Keywords: Mice, Knockout; 0301 basic medicine; Dose-Response Relationship, Drug; Beclomethasone; Drug Evaluation, Preclinical; Brain; Kidney; Permeability; 3. Good health; Androstadienes; Mice; 03 medical and health sciences; 0302 clinical medicine; Liver; Adrenal Cortex Hormones; Administration, Inhalation; Injections, Intravenous; Intubation, Intratracheal; Animals; Fluticasone; ATP Binding Cassette Transporter, Subfamily B, Member 1; Particle Size; Powders; Budesonide

Abstract The aim of this study was to evaluate if the permeability of inhaled corticosteroids entering the brain is reduced and if P-glycoprotein (P-gp) transporters are involved. Currently employed inhaled corticosteroids were given intravenously and intratracheally to rats at a dose of 100 μg kg−1. An ex-vivo receptor binding assay was used to monitor over 12 h the glucocorticoid receptor occupancy in the brain and a systemic reference organ (kidney). The involvement of P-gp in the brain permeability of triamcinolone acetonide was assessed in wild-type mice and mdr1a(-/-) knockout mice (mice lacking the gene for expressing P-gp). After both forms of administration, the average brain receptor occupancies were 20–56% of those of the reference organ, with the more lipophilic drugs showing a more pronounced receptor occupation. While the receptor occupancies in the liver of wild-type and mdr1a(-/-) mice were similar after administration of triamcinolone acetonide, brain receptor occupancies in mdr1a(-/-) mice were significantly greater (mdr1a(-/-): 47.6%, 40.2–55.0%, n = 2; wild-type: 11.5±33.0%, n = 3). Penetration into the brain for inhaled corticosteroids (especially those of lower lipophilicity) is reduced. Experiments in mdr1a(-/-) mice confirmed the involvement of P-gp transporters. Further studies are needed to assess whether potential drug interactions at the transporter level are of pharmacological significance.