Adjuvant agents enhance round window membrane permeability to dexamethasone and modulate basal to apical cochlear gradients

• Published in: European journal of pharmaceutical sciences 2019-01, Vol.126, p.69-81
• Main Authors: Creber, Nathan J., Eastwood, Hayden T., Hampson, Amy J., Tan, Justin, O'Leary, Stephen J.
• Format: Article
• Language: English
• Subjects: Absorption, Physicochemical; Adjuvants, Pharmaceutic - pharmacology; Animals; Cochlea; Cochlea - anatomy & histology; Cochlea - metabolism; Dexamethasone; Dexamethasone - pharmacokinetics; Diffusion; Drug delivery; Drug Delivery Systems; Glucocorticoids - pharmacokinetics; Glycosaminoglycans - pharmacology; Guinea Pigs; Histamine - pharmacology; Hyaluronic Acid - pharmacology; Perilymph - metabolism; Perilymph sampling; Permeability; Round Window, Ear - drug effects; Round Window, Ear - metabolism; Steroids; Tissue Distribution
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2018.08.013

Glucocorticoids have direct anti-inflammatory, anti-oxidant and anti-apoptotic effects on cochlear hair cells. Cochlear glucocorticoid therapy has gained particular attention for its ability to enhance the protection of residual hearing following hearing preservation cochlear implantation. Local drug delivery methods achieve high drug concentrations within the inner ear fluids but are reliant upon diffusion across the round window membrane. Diffusion has been shown to demonstrate large individual variability. This study explores the role of “adjuvant agents”, which when administered with glucocorticoids, enhance inner ear absorption and distribution. Guinea pig cochleae were administered either dexamethasone alone or in combination with hyaluronic acid, histamine, or combination histamine and hyaluronic acid, targeted at the round window membrane. Control subjects received saline. Perilymph was sampled from the cochlear apex, and basal to apical dexamethasone concentrations recorded with mass spectroscopy. Cochleae were harvested, and immunohistochemistry employed to explore dexamethasone tissue penetration and distribution. Basal to apical gradients were observed along the scala tympani, with higher dexamethasone concentrations observed at the cochlear base. Gradients were more pronounced and uniform when administered on a hyaluronic acid sponge, while histamine increased absolute concentrations reaching the inner ear. Tissue penetration correlated with perilymph concentration. Our results demonstrate that adjuvant agents can be employed to enhance dexamethasone absorption and distribution in the inner ear, thus proposing therapeutic strategies that may enhance steroid facilitated hearing protection. [Display omitted]