title: Permeation of losartan across human respiratory epithelium: an in vitro study with Calu-3 cells.
abstract: The potential for nasal delivery of losartan, a drug with poor oral bioavailability, was investigated using Calu-3 cells. Epithelial permeation of the drug with or without dimethyl-beta-cyclodextrin (DM-beta-CD) and glycocholate was investigated. Possible transport mechanism of the compound and epithelial mucosal tolerance were screened. Reversibility of epithelial membrane perturbation was also investigated by measuring transepithelial electrical resistance (TEER) recovery over a 24-h period following drug formulation exposure. The permeability coefficient of losartan was 1.3 + or - 0.5 x 10(-6) cm s(-1). This flux was not significantly different from that of formulations containing DM-beta-CD (0.5 and 1.0%) or glycocholate (0.5%). However, the formulation with 1.0% glycocholate significantly increased losartan permeation 7-fold. Losartan flux across the cells was concentration-dependent. Serosal to mucosal permeation was significantly higher than mucosal to serosal permeation. Concentration-dependency, as well as polarity in transport indicated that the flux of the compound across Calu-3 cells was not limited to passive diffusion. Cells exposed to DM-beta-CD (0.5 and 1.0%) and glycocholate (0.5%) caused no significant change in TEER and mitochondrial dehydrogenase activity (MDH). The results of the study showed that losartan may be a suitable drug candidate for nasal delivery.
authors.affiliation: Biopharmaceutics and Drug Delivery Laboratory, College of Pharmacy, Faculty of Health Professions, Dalhousie University, Halifax NS, Canada B3H 3J5.
authors.forename: Michelle
authors.initials: M
authors.lastname: Amoako-Tuffour
authors.forename: Pollen K
authors.initials: PK
authors.lastname: Yeung
authors.forename: Remigius U
authors.initials: RU
authors.lastname: Agu
mesh_terms: D000281:Administration, Intranasal; D001682:Biological Availability; D001692:Biological Transport; D002460:Cell Line; D006000:Glycocholic Acid; D006801:Humans; D019808:Losartan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D014677:Pharmaceutical Vehicles; D047392:beta-Cyclodextrins
chemical_list: D014677:Pharmaceutical Vehicles; D047392:beta-Cyclodextrins; C038119:heptakis(2,6-O-dimethyl)beta-cyclodextrin; D006000:Glycocholic Acid; D019808:Losartan