Aminoglycoside Ototoxicity: Influence of Dosage Regimen on Drug Uptake and Correlation between Membrane Binding and some Clinical Features

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Abstract
The influence of dosage regimen on gentamicin uptake by the inner ear tissues was investigated by radioimmunoassay in rat given single i.m. 10 or 100 mg/kg injection or i.v. 1.5 or 15 micrograms/min constant infusion. Results show that, for a given dose, discontinuous administration yields markedly lower tissue concentration than continuous administration and, thus, carries less ototoxic risk. Using 125I-labelled gentamicin as a radioligand correlation between membrane binding and clinical features was also studied in homogenates of organ of Corti and vestibular maculae of guinea-pig. Results show that: (i) as compared by Kd values, gentamicin exhibits a four-fold greater affinity for vestibule (Kd = 3 X 10(-7) M) than for cochlea (Kd = 1.2 X 10(-6) M). This explains the predilection of this antibiotic to affect the vestibular apparatus; (ii) the typical baso-lateral progression of ototoxic degeneration cannot be accounted for by a preferential uptake of the drug between base and apex.