Ototoxicity of aminoglycosides correlated with their action on monomolecular films of polyphosphoinositides

Abstract

The ototoxicities of eight aminoglycoside antibiotics and fragments were measured quantitatively by cochlear perfusion in the guinea pig. Perilymphatic spaces were perfused for 1 hr with `artificial perilymph' containing 10 mM drug, during which time continuous measurements of cochlear microphonic potentials were made. Kanamycin B and neomycin B caused the most rapid decline of cochlear microphonic potentials, followed by gentamicin C1a ~- ribostamicin > kanamycin A ~ G-418. Neamine and methylneobiosamine did not show significant effects. The same drugs were tested for their interaction with monomolecular films of polyphosphoinositides, and relative binding constants were determined. Neomycin B and kanamycin B had the highest affinities to the lipids, followed by the other drugs in the order as seen for toxicity. The correlation between the in situ and in vitro actions of the drugs was r = 0.9. These results support the hypothesis that binding to polyphosphoinositides plays an important role in the decrease of the cochlear microphonic potentials. Furthermore, the good correlation between the drug actions in the two test systems suggests that an in vitro assay may be possible for the assessment of aminoglycoside ototoxicity.