Drug Diffusion Along an Intact Mammalian Cochlea

Area of Science:

• Otic drug delivery research
• Cochlear physiology
• Pharmacokinetics

Background:

• Intratympanic drug administration relies on diffusion from the round window (RW) to the cochlear apex.
• Previous studies showed significant concentration gradients, but involved invasive cochlear manipulations.
• Passive diffusion is inherently limited along the cochlea's spiral geometry.

Purpose of the Study:

• To assess salicylate diffusion along an intact guinea pig cochlea in vivo.
• To quantify drug distribution from the RW to the cochlear apex using a novel method.
• To evaluate the feasibility of achieving uniform therapeutic drug concentrations via passive diffusion.

Main Methods:

• Utilized salicylate's suppressive effect on outer hair cell (OHC) motility to measure diffusion.
• Applied salicylate to the RW and measured auditory nerve response thresholds.
• Employed a mathematical model integrating salicylate diffusion and action on cochlear amplification.

Main Results:

• Salicylate concentrations reached steady-state over time, with longer times required for apical locations.
• Predicted steady-state salicylate concentration at the cochlear apex was negligible.
• Mathematical modeling of human cochlear geometry predicted even greater base-to-apex concentration differences.

Conclusions:

• Passive diffusion from the RW cannot achieve therapeutic drug concentrations throughout the entire cochlea.
• Significant drug concentration gradients exist between the cochlear base and apex.
• Assisted drug delivery methods are required for uniform cochlear drug distribution.