Figure 113

Renal handling of aminoglycosides: 1) glomerular filtration; 2) binding to the brush border membranes of the proximal tubule; 3) pinocytosis; and 4) storage in the lysosomes [3].

Nephrotoxicity and otovestibular toxicity remain frequent side effects that seriously limit the use of aminoglycosides, a still important class of antibiotics. Aminoglycosides are highly charged, poly-cationic, hydrophilic drugs that cross biologic membranes little, if at all [4,5]. They are not metabolized but are eliminated unchanged almost entirely by the kidneys. Aminoglycosides are filtered by the glomerulus at a rate almost equal to that of water. After entering the luminal fluid of proximal renal tubule, a small but toxicologi-cally important portion of the filtered drug is reabsorbed and stored in the proximal tubule cells. The major transport of amino-glycosides into proximal tubule cells involves interaction with acidic, negatively charged phospholipid-binding sites at the level of the brush border membrane.

After charge-mediated binding, the drug is taken up into the cell in small invaginations of the cell membrane, a process in which megalin seems to play a role [6]. Within 1 hour of injection, the drug is located at the apical cytoplasmic vacuoles, called endocy-totic vesicles. These vesicles fuse with lysosomes, sequestering the unchanged aminoglycosides inside those organelles.

Once trapped in the lysosomes of proximal tubule cells, amino-glycosides electrostatically attached to anionic membrane phospho-lipids interfere with the normal action of some enzymes (ie, phos-pholipases and sphingomyelinase). In parallel with enzyme inhibition, undigested phospholipids originating from the turnover of cell membranes accumulate in lysosomes, where they are normally digested. The overall result is lysosomal phospholipidosis due to nonspecific accumulation of polar phospholipids as "myeloid bodies," so called for their typical electron microscopic appearance. (Adapted from De Broe [3].)

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