Characterization of aminoglycoside-lipid interactions and development of a refined model for ototoxicity testing

Abstract

Aminoglycoside interactions with various phospholipids were measured in three model systems and compared with the ototoxicities of the drugs: (a) competition for [ 14C]neomycin binding; (b) competition for 45Ca 2+ binding; and (c) effect on surface pressure of monomolecular lipid films. The efficacies of the antibiotics in displacing neomycin from phosphatidylserine, phosphatidylinositol or phosphatidylinositol bisphosphate were netilmicin > neomycin ⩾ gentamicin; the efficacies in displacing calcium from phosphatidylinositol, phosphatidylinositol phosphate or phosphatidylinositol bisphosphate were netilmicin > gentamicin > neomycin > kanamycin > spectinomycin. Neither measure correlated well with the ototoxicities of the drugs which were quantitated at equimolar drug concentrations in cochlear perfusions: neomycin > gentamicin ≥ tobramycin > netilmicin ≥ amikacin. When monomolecular films of phosphatidylcholine with phosphatidylserine, cardiolipin, phosphatidylinositol, or phosphatidylinositol phosphate or bisphosphate were challenged with neomycin, the phosphatidylinositol bisphosphate film showed a unique dose-dependent increase in surface pressure while the others showed a decrease or no significant effect. The abilities of aminoglycosides to increase the surface pressure of a film of phosphatidycholine : phosphatidylinositol bisphosphate (1:1 molar ratio) in the presence of 3 mM CaCl 2 correlated well with their toxicities. Non-ototoxic cations increased the film pressure or left it unaffected. The results confirm the unique interactions between aminoglycosides and phosphatidylinositol bisphosphate as a possible basis of a mechanism of toxicity and development of a drug-screening system.