Probenecid reduces cochlear effects and perilymph penetration of furosemide in chinchilla

Previous investigation has suggested that the ototoxicity of furosemide is related to penetration of the drug into the inner ear and that active drug transport out of the inner ear may be responsible for maintaining the serum-perilymph drug concentration gradient. We further tested this hypothesis by investigating the endocochlear potential (ototoxicity) and furosemide perilymph concentrations after furosemide administration to chinchillas pretreated with the organic anion transport inhibitor, probenecid. Probenecid pretreatment attenuated the fall in endocochlear potential seen after furosemide (25 mg/kg i.v.): untreated, 58.6 +/- 27.0 mV; probenecid pretreatment, 14.1 +/- 11.9 mV (P less than .01). Furosemide concentrations in perilymph were correspondingly lower after probenecid (P less than .003), although serum furosemide concentrations were not affected by probenecid pretreatment. Diuresis, measured over an 8-hr period after furosemide, was also uneffected by probenecid. These results confirm the proposed relationship between inner ear furosemide concentrations and the occurrence of ototoxicity due to this drug. However, the determinants of penetration of this drug into the inner ear are unclear. The observation that probenecid pretreatment attenuates the ototoxic effect of furosemide while the diuretic effect is preserved suggests this drug combination warrants further investigation.