Drug diffusion along an intact mammalian cochlea

Ildar I. Sadreev, George W.S. Burwood, Samuel M. Flaherty, Jongrae Kim, Ian J. Russell, Timur I. Abdullin, Andrei N. Lukashkin

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number161
JournalFrontiers in Cellular Neuroscience
Volume13
DOIs
Publication statusPublished - 26 Apr 2019

Fingerprint

Cochlea
Salicylates
Pharmaceutical Preparations
Perilymph
Membranes
Outer Auditory Hair Cells
Cochlear Aqueduct
Cochlear Duct
Cochlear Nerve
Cell Movement
Permeability
Adrenal Cortex Hormones
Guinea Pigs
Theoretical Models
Ions
Anti-Bacterial Agents

Bibliographical note

Copyright © 2019 Sadreev, Burwood, Flaherty, Kim, Russell, Abdullin and Lukashkin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance
with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Keywords

  • Cochlea
  • Cochlear amplifier
  • Cochlear round window
  • Drug delivery
  • Salicylate

Cite this

Sadreev, Ildar I. ; Burwood, George W.S. ; Flaherty, Samuel M. ; Kim, Jongrae ; Russell, Ian J. ; Abdullin, Timur I. ; Lukashkin, Andrei N. / Drug diffusion along an intact mammalian cochlea. In: Frontiers in Cellular Neuroscience. 2019 ; Vol. 13.
@article{dad4570fd5024ed3a804afc7cc16d557,
title = "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.",
keywords = "Cochlea, Cochlear amplifier, Cochlear round window, Drug delivery, Salicylate",
author = "Sadreev, {Ildar I.} and Burwood, {George W.S.} and Flaherty, {Samuel M.} and Jongrae Kim and Russell, {Ian J.} and Abdullin, {Timur I.} and Lukashkin, {Andrei N.}",
note = "Copyright {\circledC} 2019 Sadreev, Burwood, Flaherty, Kim, Russell, Abdullin and Lukashkin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.",
year = "2019",
month = "4",
day = "26",
doi = "10.3389/fncel.2019.00161",
language = "English",
volume = "13",
journal = "Frontiers in Cellular Neuroscience",
issn = "1662-5102",

}

Drug diffusion along an intact mammalian cochlea. / Sadreev, Ildar I.; Burwood, George W.S.; Flaherty, Samuel M.; Kim, Jongrae; Russell, Ian J.; Abdullin, Timur I.; Lukashkin, Andrei N.

In: Frontiers in Cellular Neuroscience, Vol. 13, 161, 26.04.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Drug diffusion along an intact mammalian cochlea

AU - Sadreev, Ildar I.

AU - Burwood, George W.S.

AU - Flaherty, Samuel M.

AU - Kim, Jongrae

AU - Russell, Ian J.

AU - Abdullin, Timur I.

AU - Lukashkin, Andrei N.

N1 - Copyright © 2019 Sadreev, Burwood, Flaherty, Kim, Russell, Abdullin and Lukashkin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

PY - 2019/4/26

Y1 - 2019/4/26

N2 - 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.

AB - 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.

KW - Cochlea

KW - Cochlear amplifier

KW - Cochlear round window

KW - Drug delivery

KW - Salicylate

UR - http://www.scopus.com/inward/record.url?scp=85066955125&partnerID=8YFLogxK

U2 - 10.3389/fncel.2019.00161

DO - 10.3389/fncel.2019.00161

M3 - Article

VL - 13

JO - Frontiers in Cellular Neuroscience

JF - Frontiers in Cellular Neuroscience

SN - 1662-5102

M1 - 161

ER -