HYPOTHESIS: That a theoretical basis for quantifying drug distribution in the inner ear with local applications can be established. BACKGROUND: As methods of local drug delivery to the inner ear gain wider clinical acceptance it becomes important to establish how drugs are distributed in the ear as a function of time and for different delivery methods. METHODS: The time course of gentamicin concentration in the inner ear fluids was simulated with a program that considered general pharmacokinetic principles and incorporated inner ear dimensions and drug dispersal processes, including diffusion, clearance, and intercompartmental exchange. RESULTS: Cochlear fluid space dimensions of the chinchilla were derived from three-dimensional magnetic resonance images and were incorporated into the simulator. The published time course of gentamicin in vestibular perilymph of chinchillas was closely approximated by the adjustment of parameters defining round window membrane permeability, clearance, and interscala exchange. To simulate the time course, it was necessary for drug entry into the vestibule to be dominated by interscala exchange rather than longitudinal spread through the helicotrema. The effects of different round window delivery methods were also calculated. Perilymph drug levels and spatial distribution in the ear were shown to be markedly influenced by the time the applied drug remained in the middle ear. CONCLUSION: The development of local inner ear drug application strategies requires consideration of inner ear pharmacokinetic characteristics, delivery methods, and therapeutic range of the drug.
HYPOTHESIS: That a theoretical basis for quantifying drug distribution in the inner ear with local applications can be established. BACKGROUND: As methods of local drug delivery to the inner ear gain wider clinical acceptance it becomes important to establish how drugs are distributed in the ear as a function of time and for different delivery methods. METHODS: The time course of gentamicin concentration in the inner ear fluids was simulated with a program that considered general pharmacokinetic principles and incorporated inner ear dimensions and drug dispersal processes, including diffusion, clearance, and intercompartmental exchange. RESULTS: Cochlear fluid space dimensions of the chinchilla were derived from three-dimensional magnetic resonance images and were incorporated into the simulator. The published time course of gentamicin in vestibular perilymph of chinchillas was closely approximated by the adjustment of parameters defining round window membrane permeability, clearance, and interscala exchange. To simulate the time course, it was necessary for drug entry into the vestibule to be dominated by interscala exchange rather than longitudinal spread through the helicotrema. The effects of different round window delivery methods were also calculated. Perilymph drug levels and spatial distribution in the ear were shown to be markedly influenced by the time the applied drug remained in the middle ear. CONCLUSION: The development of local inner ear drug application strategies requires consideration of inner ear pharmacokinetic characteristics, delivery methods, and therapeutic range of the drug.
Authors: David A Borkholder; Xiaoxia Zhu; Brad T Hyatt; Alfredo S Archilla; William J Livingston; Robert D Frisina Journal: Hear Res Date: 2010-05-06 Impact factor: 3.208