title: Brain permeability of inhaled corticosteroids.
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 microg 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=14; 2; wild-type: 11.5+/-33.0%, n=14; 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.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Arya
authors.forename: Manish
authors.initials: M
authors.lastname: Issar
authors.forename: Yaning
authors.initials: Y
authors.lastname: Wang
authors.forename: James D
authors.initials: JD
authors.lastname: Talton
authors.forename: Guenther
authors.initials: G
authors.lastname: Hochhaus
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001507:Beclomethasone / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D019819:Budesonide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D000068298:Fluticasone; D007275:Injections, Intravenous; D007442:Intubation, Intratracheal; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010316:Particle Size; D010539:Permeability / Q000187:drug effects; D011208:Powders; D011355:Prodrugs / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011987:Receptors, Steroid / Q000187:drug effects; D013045:Species Specificity; D013997:Time Factors; D014222:Triamcinolone Acetonide / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000305:Adrenal Cortex Hormones; D000730:Androstadienes; D011208:Powders; D011355:Prodrugs; D011987:Receptors, Steroid; D019819:Budesonide; D000068298:Fluticasone; D014222:Triamcinolone Acetonide; D001507:Beclomethasone