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The renal handling of polybasic drugs

1. Gentamicin and aprotinin in intact animals

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Summary

Upon intravenous injection of 3H-gentamicin in rats, radioactivity in serum rapidly declined to 3% of total within 1 h. Kidneys accumulated a constant amount (14%) of the injected radioactivity between 2 and 6 h after injection.

In mice, simultaneous or prior application of unlabeled gentamicin (10 mg/kg) diminished the renal concentration of 3H-gentamicin, and aprotinin (10 mg/kg) was able to compete with labeled aprotinin. Aprotinin did not diminish the renal accumulation of gentamicin and vice versa. However, since 10 mg/kg aprotinin raised also the plasma concentrations of both 3H-gentamicin and 125I-aprotinin, the evidences resulting from these experiments are limited.

Mouse kidney cortex was processed for light and electron microscopic autoradiography at different times following i.v. injection of 3H-gentamicin. Gentamicin enters the apical part of proximal tubule cells. Initially, brush border and basement membrane labeling is prominent, whereas lysosomes appear as intense and prevalent stores 20 min or later after injection.

Fractionation of 3H-gentamicin loaded kidneys showed a similar distribution pattern of radioactivity and the lysosomal marker β-galactosidase. The same was true when the crude lysosomal fraction was subjected to density gradient centrifugation, which corroborates the microscopical findings. Radioactivity is partially bound to lysosomal structures, for repeated freezing of loaded lysosomes left 35% of radioactivity particle-bound.

It is concluded that both gentamicin and peptides are handled in a similar manner by adsorption, followed by endocytosis and lysosomal sequestration in proximal tubule cells.

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References

  • Alfthan, O., Renkonen, O. V., Sivonen, A.: Concentration of gentamicin in serum, urine and urogenital tissue in man. Acta Path. Microbiol. Scand., Section B 81, Suppl. 241, 92–94 (1973)

    Google Scholar 

  • Ascoli, M., Liddle, R. A., Puett, D.: Renal and hepatic lysosomal catabolism of luteinizing hormone. Mol. Cell. Endocrinol. 4, 297–310 (1976)

    Google Scholar 

  • Bennett, W. M., Hartnett, M. N., Gilbert, D., Houghton, D., Porter, G. A.: Effect of sodium intake on gentamicin nephrotoxicity in the rat. Proc. Soc. Exp. Biol. Med. 151, 736–738 (1976)

    Google Scholar 

  • Bergan, T., Brodwall, E. K., Westlie, L., Oyri, A.: Renal excretion of gentamicin and effect of probenecid. Acta Path. Microbiol. Scand., Section B 81, Suppl. 241, 95–98 (1973)

    Google Scholar 

  • Black, J., Calesnick, B., Williams, D., Weinstein, M. J.: Pharmacology of gentamicin, a new broad-spectrum antibiotic. Antimicrob. Agents Chemother. 138–147 (1963)

  • Bode, F., Baumann, K., Kinne, R.: Analysis of the pinocytic process in rat kidney. II. Biochemical composition of pinocytic vesicles compared to brush border microvilli, lysosomes and basolateral plasma membranes. Biochim. Biophys. Acta 433, 294–310 (1976)

    Google Scholar 

  • Bourdeau, J. E., Carone, F. A.: Protein handling by the renal tubule. Nephron 13, 22–34 (1974)

    Google Scholar 

  • Chiu, P. J. S., Brown, A., Miller, G., Long, J. F.: Renal extraction of gentamicin in anesthetized dogs. Antimicrob. Agents Chemother. 10, 277–282 (1976)

    Google Scholar 

  • Christensen, E. I.: Rapid protein uptake and digestion in proximal tubule lysosomes. Kidney Int. 10, 301–310 (1976)

    Google Scholar 

  • Cortney, M. A., Sawin, L. L., Weiss, D. D.: Renal tubular protein absorption in the rat. J. Clin. Invest. 49, 1–4 (1970)

    Google Scholar 

  • Ericsson, J. L. E.: Electron microscopy of renal tubule degeneration. Meth. Achievm. Exp. Path. 4, 171–213 (1969)

    Google Scholar 

  • Fabre, J., Rudhardt, M., Blanchard, P., Regamey, C.: Persistence of sisomicin and gentamicin in renal cortex and medulla compared with other organs and serum of rats. Kidney Int. 10, 444–449 (1976)

    Google Scholar 

  • Gyselynck, A.-M., Forrey, A., Cutler, R.: Pharmacokinetics of gentamicin: distribution and plasma and renal clearance. J. Infect. Dis. 124, Suppl., S 70–76 (1971)

    Google Scholar 

  • Habermann, E.: Transmembranal and intracellular transport of pharmacologically active proteins and polypeptides. Naunyn-Schmiedeberg's Arch. Pharmacol. 297, 11–14 (1977)

    Google Scholar 

  • Houghton, D. C., Hartnett, M., Campbell-Boswell, M., Porter, G., Bennett, W.: A light and electron microscopic analysis of gentamicin nephrotoxicity in rats. Am. J. Pathol. 82, 589–612 (1976)

    Google Scholar 

  • Just, M.: In vivo interaction of the Kunitz protease inhibitor and of insulin with subcellular structures from rat renal cortex. Naunyn-Schmiedeberg's Arch. Pharmacol. 287, 85–95 (1975)

    Google Scholar 

  • Just, M., Habermann, E.: Interactions of a protease inhibitor and other peptides with isolated brush border membranes from rat renal cortex. Naunyn-Schmiedeberg's Arch. Pharmacol. 280, 161–176 (1973)

    Google Scholar 

  • Just, M., Habermann, E.: The renal handling of polybasic drugs. 2. In vitro studies with brush border and lysosomal preparations. Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 67–76

  • Lode, H., Kemmerich, B., Koeppe, P.: Comparative clinical pharmacology of gentamicin, sisomicin, and tobramycin. Antimicrob. Agents Chemother. 8, 396–401 (1975)

    Google Scholar 

  • Luft, F. C., Kleit, S. A.: Renal parenchymal accumulation of aminoglycoside antibiotics in rats. J. Infect. Dis. 130, 656–659 (1974)

    Google Scholar 

  • Luft, F. C., Patel, V., Yum, M. N., Patel, B., Kleit, S. A.: Experimental aminoglycoside nephrotoxicity. J. Lab. Clin. Med. 86, 213–220 (1975)

    Google Scholar 

  • Maack, T.: Renal handling of low molecular weight proteins. Am. J. Med. 58, 57–64 (1975)

    Google Scholar 

  • Maunsbach, A. B.: Functions of lysosomes in kidney cells. In: Lysosomes in biology and pathology, Vol. 1, pp. 115–154. Ed. by J. T. Dingle and H. B. Fell. Amsterdam: North-Holland 1969

    Google Scholar 

  • Maunsbach, A. B.: Ultrastructure of the proximal tubule. In: Handbook of Physiology. Section 8, pp. 31–79. Ed. by J. Orloff and W. R. Berliner. Washington: Am. Phys. Soc. 1973

    Google Scholar 

  • Miller, F., Palade, G. E.: Lytic activities in renal protein absorption droplets. An electron microscopical cytochemical study. J. Cell Biol. 23, 519–552 (1964)

    Google Scholar 

  • Nedden, R., Fuchs, T., Schröder, K., Wundt, W.: Die renale Ausscheidung von Gentamicin beim Menschen. Dtsch. Med. Wochenschr. 97, 1496–1503 (1972)

    Google Scholar 

  • Oliver, J., MacDowell, M., Lee, Y. C.: Cellular mechanism of protein in the nephron. J. Exp. Med. 99, 589–605 (1954)

    Google Scholar 

  • Robinson, D., Price, R. G., Dance, N.: Separation and properties of β-galactosidase, β-glucosidase, β-glucuronidase, and N-acetyl-β-glucosaminidase from rat kidney. Biochem. J. 102, 525–532 (1967)

    Google Scholar 

  • Ryser, H. J.-P.: Uptake of protein by mammalian cells: An under-developed area. Science 159, 390–396 (1968)

    Google Scholar 

  • Shipko, S., Tappel, A. L.: Rat-kidney lysosomes: Isolation and properties. Biochem. J. 95, 731–741 (1965)

    Google Scholar 

  • Straus, W.: Rapid cytochemical identification of phagosomes in various tissues of the rat and their differentiation from mitochondria by the peroxidase method. J. Biophysic. Biochem. Cytol. 5, 193–203 (1959)

    Google Scholar 

  • Straus, W.: Comparative analysis of the concentration of injected horseradish peroxidase in cytoplasmic granules of the kidney cortex, in the blood, urine, and liver. J. Cell Biol. 48, 620–632 (1971)

    Google Scholar 

  • Strober, W., Waldmann, T. A.: The role of the kidney in the metabolism of plasma proteins. Nephron 13, 35–66 (1974)

    Google Scholar 

  • Swed, J. J., Luft, F., Black, H. R., Elliott, R. A., Kleit, S. A.: Comparison of the distribution of tobramycin and gentamicin in body fluids of dogs. Antimicrob. Agents Chemother. 5, 444–446 (1974)

    Google Scholar 

  • Thoenes, W., Langer, K. H., Pfeiffer, U., Romen, W.: Eiweißresorptionstropfen und Lysosomen im proximalen Tubuluskonvolut der Ratteniere. Virchows Arch., Abt. B Zellpath. 5, 124–143 (1970)

    Google Scholar 

  • Thomas, A. H., Tappin, S. D.: Separation of gentamicin complex by ion exchange chromatography. J. Chromatog. 97, 280–283 (1974)

    Google Scholar 

  • Török, P.: Die Lokalisation eines Proteinasen-Inhibitors in der Niere der Maus durch Immunfluoreszenz. Arzneim.-Forsch. (Drug Res.) 22, 1534–1538 (1972)

    Google Scholar 

  • Trautschold, I., Werle, E., Fritz, H.: Zur Biochemie des Trasylol. In: Neue Aspekte der Trasylol-Therapie, Vol. 1, pp. 3–19. Stuttgart: Schattauer, 1966

    Google Scholar 

  • Ullrich, K. J.: Renal tubular mechanisms of organic solute transport. Kidney Int. 9, 134–148 (1976)

    Google Scholar 

  • Vera-Roman, J., Krishnakantha, T. P., Cuppage, F. E.: Gentamicin nephrotoxicity in rats. I. Acute biochemical and ultra-structural effects. Lab. Invest. 33, 412–417 (1975)

    Google Scholar 

  • Wahlig, H., Metallinos, A., Hameister, W., Bergmann, R.: Gentamicin-Konzentrationen in Geweben und Körperflüssigkeiten von Versuchstieren. Int. J. Clin. Pharmacol. 10, 212–229 (1974)

    Google Scholar 

  • Whelton, A., Carter, G. G., Bryant, H. H.: Therapeutic implications of gentamicin accumulation in severely diseased kidneys. Arch. Intern. Med. 136, 172–176 (1976)

    Google Scholar 

  • Wilson, T. W., Mahon, W. A., Inaba, T., Johnson, G. E., Kadar, D.: Elimination of tritiated gentamicin in normal human subjects and in patients with severely impaired renal function. Clin. Pharmacol. Therap. 14, 815–822 (1973)

    Google Scholar 

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Authors and Affiliations

  1. Pharmakologisches Institut der Justus Liebig-Universität Giessen, Frankfurter Strasse 107, D-6300, Lahn-Giessen, Federal Republic of Germany

    Melitta Just, G. Erdmann & E. Habermann

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  1. Melitta Just
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  2. G. Erdmann
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  3. E. Habermann
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Additional information

Some preliminary data were given at the Congress of the German Pharmacological Society, Hannover, 1976 (Habermann, 1977)

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Just, M., Erdmann, G. & Habermann, E. The renal handling of polybasic drugs. Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 57–66 (1977). https://doi.org/10.1007/BF00505080

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  • DOI: https://doi.org/10.1007/BF00505080

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