Pharmacologic determinants of ototoxicity of furosemide in the chinchilla

The commonly used diuretic furosemide (FSM) may clinically produce transient hearing impairment by a disruption of endocochlear potential. We have examined the possibility that this ototoxicity is produced by direct FSM penetration into the cochlea by assessing the determinants of FSM penetration into cochlear fluid (perilymph), determining the pharmacokinetics of the drug in serum and perilymph and comparing the time courses of cochlear drug concentration and ototoxicity. The highest FSM concentrations in perilymph were found 15 min after an ototoxic dose of FSM (100 mg/kg). Elimination of the drug from perilymph paralleled that from serum, and a 65:1 drug concentration gradient (serum/perilymph) was rapidly established and maintained. The same gradient was found after other ototoxic FSM doses (25-200 mg/kg) and after chronic FSM administration. The magnitude of this gradient could not be accounted for by binding of FSM to serum proteins, by pH-dependent drug partitioning or by cochlear drug glucuronidation. The drug elimination profile from perilymph was most consistent with free penetration of drug into the inner ear coupled with rapid removal. The time course of endocochlear potential depression was strikingly similar to the FSM-perilymph concentration time curve; maximal endocochlear potential depression occurred at 5 to 15 min after the intravenous dose, corresponding with the time of peak perilymph FSM levels, but not with local diuretic effects on electrolytes. Calculations based on the pharmacokinetic data revealed that FSM produced depression of endocochlear potential only at doses sufficient to produce FSM perilymph concentrations greater than 1.3 μg/ml. Furthermore, this potential remained depressed only as long as the local FSM concentration exceeded this same threshold value. The observations are consistent with the hypothesis that the ototoxicity of FSM is related directly to drug penetration rather than mediated through secondary effects on electrolytes.