Drug Diffusion Along an Intact Mammalian Cochlea

Abstract

Intratympanic drug administration depends on the ability of drugs to pass through the round window membrane (RW) at the base of the cochlea and diffuse from this location to the apex. While the RW permeability for many different drugs can be promoted, passive diffusion along the narrowing spiral of the cochlea is limited. Earlier measurements of the distribution of marker ions, corticosteroids, and antibiotics demonstrated that the concentration of substances applied to the RW was two to three orders of magnitude higher in the base compared to the apex. The measurements, however, involved perforating the cochlear bony wall and, in some cases, sampling perilymph. These manipulations can change the flow rate of perilymph and lead to intake of perilymph through the cochlear aqueduct, thereby disguising concentration gradients of the delivered substances. In this study, the suppressive effect of salicylate on cochlear amplification via block of the outer hair cell (OHC) somatic motility was utilized to assess salicylate diffusion along an intact guinea pig cochlea in vivo . Salicylate solution was applied to the RW and threshold elevation of auditory nerve responses was measured at different times and frequencies after application. Resultant concentrations of salicylate along the cochlea were calculated by fitting the experimental data using a mathematical model of the diffusion and clearing of salicylate in a tube of variable diameter combined with a model describing salicylate action on cochlear amplification. Concentrations reach a steady-state at different times for different cochlear locations and it takes longer to reach the steady-state at more apical locations. Even at the steady-state, the predicted concentration at the apex is negligible. Model predictions for the geometry of the longer human cochlea show even higher differences in the steady-state concentrations of the drugs between cochlear base and apex. Our findings confirm conclusions that achieving therapeutic drug concentrations throughout the entire cochlear duct is hardly possible when the drugs are applied to the RW and are distributed via passive diffusion. Assisted methods of drug delivery are needed to reach a more uniform distribution of drugs along the cochlea.

Dose-Dependent Transient Decrease of Impedances by Deep Intracochlear Injection of Triamcinolone With a Cochlear Catheter Prior to Cochlear Implantation–1 Year Data

“…Based on knowledge from mouse cochleae, especially the diffusion of drugs from the base to the apex may be influenced by clearance and by transport between the scalae (23,24). However, the data obtained for cochlear pharmacokinetics are mainly based on animal experiments and on transtympanic but not intracochlear drug delivery (17,(23)(24)(25).…”

Local Drug Delivery to the Entire Cochlea without Breaching Its Boundaries

“…Salicylate did not cause elevation of the CAP threshold responses for frequencies below 5 kHz, which corresponds to about 45% of the total cochlear length from the base, when it diffused through the cochlea passively (Sadreev et al, 2019). The calculated gradient of base-to-apex salicylate concentration was about 13 orders of magnitude.…”

“…The threshold elevation saturated after 4-5 cycles of CP, even for the low frequencies of the most apical locations (Figures 1B and 2, 1-3 kHz) where passive diffusion produced no effect. Smaller threshold elevations at low frequencies were due only to the reduced contribution of cochlear amplification to cochlear responses at these frequencies (Sadreev et al, 2019;Robles and Ruggero, 2001) and, in fact, reached almost maximal possible elevations for those frequencies (Figure 3).…”

“…The ability to distribute drugs uniformly along the entire cochlear spiral using relatively large, lowfrequency periodic displacement of fluid in the ST and SV was demonstrated in our experiments with application of salicylate to the RW. Salicylate readily passes through the RW (Borkholder et al, 2014;Sadreev et al, 2019). To monitor salicylate diffusion along an intact guinea pig cochlea in vivo, we utilized the suppressive effect of salicylate on cochlear amplification by blocking the outer hair cell somatic motility (Russell and Schauz, 1995;Hallworth, 1997).…”

“…Hydrogel-based drug delivery systems also allow retention of therapeutics in the middle ear in contact with the RW. The problem with this strategy is that retention of drugs at the RW leads to their establishing steady-state concentration gradients along the cochlea, which depend on the relationship between diffusion and clearing (Salt and Ma, 2001;Sadreev et al, 2019), but the base-to-apex gradients can still be very pronounced.…”