Nutritional status, glutathione levels, and ototoxicity of loop diuretics and aminoglycoside antibiotics

Chinchillas deprived of food for 48 h prior to the administration of a combined dose of ethacrynic acid (10 mg/kg) and kanamycin (100 mg/kg) suffered a profound hearing loss. Fed animals did not demonstrate any hearing loss at the same dose levels. Drug metabolism may be the common pathway by which ototoxic agents interact, by a mechanism which is common to both the cochlea and the kidney. Glutathione (GSH) is a tripeptide which is involved in several pathways in the detoxification of active oxygen and reactive species formed during xenobiotic metabolism. The enhanced auditory dysfunction was paralleled by one-third decline in hepatic glutathione levels in the food-deprived animals. Manipulation of endogenous GSH levels may mitigate the toxicities of many of these drugs, which otherwise limit their clinical usefulness. These results also indicate that nutritional status may have important clinical implications during drug therapy.