Uptake and Subcellular Distribution of Poly-L-Aspartic Acid, a Protectant Against Aminoglycoside-Induced Nephrotoxicity, in Rat Kidney Cortex

Abstract

Williams & Hottendorf (1985), and Williams et al. (1986) have observed that the co-administration of poly-L-aspartic acid protects rats against gentamicin or amikacin-induced nephrotoxicity. Yet, they found that coadministration of polyaspartic acid increased the total amount of aminoglycoside accumulated by kidney cortex, although less drug was recovered in fractions enriched in brush-border and basolateral membranes. We showed that polyaspartic acid significantly protects against gentamicin-induced lysosomal phospholipidosis (Beauchamp et al., 1986), an early renal alteration which we previously demonstrated to be a specific and predictive index of aminoglycoside nephrotoxicity related to the accumulation of the these drugs in lysosomes (see Tulkens et al., 1985, and Tulkens, 1986, for review). Beauchamp et al. (1986), and more recently Gilbert et al. (1987) also confirmed that polyaspartic acid did not decrease, but rather increased the amount of gentamicin stored by kidney cortex. The latter results are in contradiction with the original hypothesis of Williams & Hottendorf (1985) who selected polyaspartic acid as a potential competitor for gentamicin uptake by kidney, based on the observation that it interferes with gentamicin binding to renal membrane vesicles in vitro.