Brain permeability of inhaled corticosteroids

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
DOI: 10.1211/jpp.57.9.0010 Publication Date: 2005-08-04T22:50:15Z
ABSTRACT
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.
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