In vitro prediction of aminoglycoside ototoxicity

Abstract

The first step by which a basic aminoglycoside (AG) causes ototoxicity is thought to be electron binding to such acidic substances as phosphatidylinositol diphosphate and acidic glycosaminoglycans (AGAGs). We studied the competitive binding ability of AGs and basic dyes to AGAG in order to determine if this mechanism was indeed responsible for ototoxicity. The negative charge of heparin was the strongest among the AGAGs examined when the molar ratio of AG to AGAG was small. Toluidine blue was a better basic dye than acridine orange, methylene blue, alcian blue, or neutral red. After we mixed toluidine blue, heparin and an AG, the absorbance of free toluidine blue was measured at 625 nm. The difference in the free dye released by the well-established AG showed a fairly good correlation with the ototoxic activity found in vivo. However, the predicted ototoxicities of newly prepared AGs were greater than estimated when testing their effects on experimental animals. The basicity of AGs will determine their binding affinities to cochlear hair cell membranes and is an important factor in predicting ototoxicity.

Vestibular and Cochlear Toxicity of Aminoglycosides - A review

“…Saito et al (27) considered that bond formation between a basic aminoglycoside and acidic substances, such as phosphatidylinosito l bisphosphate and acidic glycosaminoglycans , is the ® rst step towards ototoxicity. Various studies have been undertaken to investigate the strength of this binding, to evaluate whether aminoglycoside ototoxicity can be anticipated in ×itro.…”

“…Various studies have been undertaken to investigate the strength of this binding, to evaluate whether aminoglycoside ototoxicity can be anticipated in ×itro. Saito et al (27) studied the competitive binding ability of aminoglycosides and basic dyes to heparin, as a representative of acidic glycosaminoglycans . After mixing the aminoglycoside, heparin and the basic dye, toluidine blue, they measured the absorbance of free toluidine blue at 625 nm.…”