Rats were injected with 25 microCi (14.2 microgram) of tritiated gentamicin and were killed 10 min, 1 hour, or 24 hours after the injection. Renal tissue was preserved by intravascular perfusion of a glutaraldehyde-containing solution. In a preliminary experiment, glutaraldehyde was found to fix gentamicin to bovine serum albumin, and this property probably accounted for the negligible loss of label during specimen preparation. By light microscopy, gentamicin appeared to be confined almost entirely to the proximal tubules. Autoradiographic grains appeared initially over the apical cytoplasm of the proximal tubule cells and, with time, moved progressively into the interior of the cell. Electron-microscopy revealed that the grains were associated with apical vesicles at 10 min and lysosomes at 1 and 24 hours. The specificity of labeling was confirmed by quantitative grain analysis. These results indicate that gentamicin is transported into the proximal tubule cell by pinocytosis and becomes sequestered in lysosomes. This process may account for the accumulation of myeloid bodies in the proximal tubule lysosomes of gentamicin-treated rats, but whether this mechanism contributes the nephrotoxicity of this drug cannot be ascertained at this time.
Multiple factors may modify the pharmacokinetics of aminoglycosides and affect their nephrotoxic potential. In the present study, the influence of Escherichia coli pyelonephritis on the renal handling of [3H]tobramycin was investigated. The accumulation of [3H]tobramycin in proximal and distal tubules in both normal and infected rats was compared. Following induction of pyelonephritis, disturbed intrarenal localization of the drug was noted. Grain counts were affected in both proximal and distal tubules. Decreased labeling was observed at all time intervals in the proximal tubules. Electron microscopy showed that radioactivity was associated mostly with lysosomes in both normal and infected rats 1 and 24 h following the injection of the drug. We could detect significantly higher amounts of drug in the distal tubules of the pyelonephritic kidney than the normal levels at 10 min and 24 h postinjection. The drug did not seem to be associated with any particular organelle and was evenly distributed within the distal tubular cells. The present study shows that the transport of tobramycin within the infected nephron is disturbed. These data might shed some light on the influence of infection on the intrarenal pharmacology of aminoglycosides.To understand the mechanism of cellular accumulation as well as the cellular transport of aminoglycosides, several investigators have studied the intrarenal disposition of gentamicin by autoradiography (11,18,20). Coupled with electron microscopy, this technique has the unique advantage of allowing recognition of the presence of a labeled compound within tissue and individual cell organelles.The autoradiographic studies that have been done to date agree that the proximal tubule is the primary site of aminoglycoside accumulation. According to the results of these studies, aminoglycosides are generally believed to enter proximal tubule cells by pinocytosis at the luminal cell membrane, with subsequent fusion of endocytotic vacuoles with lysosomes (18,20).No one, however, has yet studied the transport of antibiotics in infected kidneys. On the basis of our previous data, which showed that the intrarenal concentrations of aminoglycosides were disturbed in pyelonephritis (4), we had reason to believe that the distribution of antibiotics, especially aminoglycosides, is disturbed in infected kidneys. tion of the left kidney with 0.1 ml of an inoculum containing 107 to 108 CFU of Escherichia coli Yale. The right kidney was infected by reflux of infected urine into the right ureter, rats being naturally prone to vesico-ureteral reflux. Six uninjected animals served as controls. The animals then had free access to standard rat chow and water. At 4 days after the induction of pyelonephritis, all infected and normal animals were anesthetized with pentobarbital (50 mg/kg of body weight). Polyethylene PE-20 catheters were placed in a jugular vein for intravenous infusions.Each rat was injected intravenously with 50 ,uCi (13 ,ug) of tritiated tobramycin (>2.0 Ci/mmol; 98% pure by thin-layer chrom...
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