Quantification of solute entry into cochlear perilymph through the round window membrane

The administration of drugs to the inner ear via the round window membrane is becoming more widely used for both clinical and experimental purposes. T he actual drug levels achieved in different regions of the inner ear by thi s method have not been established. The present study has made use of simul ations of solute movements in the cochlear fluids to describe the distribut ion of a marker solute in the guinea pig cochlear fluid spaces. Simulation parameters were derived from experimental measurements using a marker ion. trimethylphenylammonium (TMPA). The distribution of this ion in the cochlea was monitored without volume disturbance using TMPA-selective microelectro des sealed into the first and second turns of scala tympani (ST). TMPA was applied to perilymph by irrigation of the intact round window membrane with 2 mM solution. At the end of a 90 min application period, TMPA in the firs t turn, 1.4 mm from the base of ST, reached an average concentration of 330 muM (standard deviation (S.D.) 147 muM, n = 8). TMPA in the second turn. 7 .5 mm from the base of ST reached a concentration of 15 muM (S.D. 33 muM, n = 5). The measured time courses of TMPA concentration change were interpre ted using the Washington University Cochlear Fluids Simulator (V 1.4), a pu blic-domain program available on the internet at http://oto.wustl.edu/cochl ea/. Simulations with parameters producing concentration time courses compa rable to those measured were: (1) round window permeability: 1.9X10(-8) cm/ s; (2) ST clearance half-time: 60 min: (3) longitudinal perilymph flow rate : 4.4 nl/min, directed from base to apex. Solute concentrations in apical r egions of the cochlea were found to be determined primarily by the rate at which the solute diffuses, balanced by the rate of clearance of the solute from perilymph. Longitudinal perilymph now was not an important factor in s olute distribution unless the bony otic capsule was perforated. which rapid ly caused substantial changes to solute distribution. This study demonstrat es the basic processes by which substances are distributed in the cochlea a nd provides a foundation to understand how other applied substances will be distributed in the ear. (C) 2001 Elsevier Science B.V. All rights reserved .