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The renal handling of polybasic drugs

2. In vitro studies with brush border and lysosomal preparations

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Summary

  1. 1.

    Experiments with Brush Border Membranes

    Drugs were screened for inhibition of 125I-aprotinin binding to isolated rat renal brush border membranes. Cationic polymers were effective, and their primary amino groups were crucial. The polycationic aminoglycosides displaced 125I-aprotinin with low concentrations (50% inhibition by 50 μg/ml of gentamicin). The decreasing sequence of both number of amino groups and of inhibitory potency was: neomycin > tobramycin > gentamicin > kanamycin > streptomycin.

    Binding of 3H-gentamicin-C1 to the brush border membrane was saturable. The Scatchard plot indicated an association constant of 43 mM−1, and 18 nmoles per mg of membrane protein for the number of binding sites.

    Inhibition of 125I-aprotinin binding by gentamicin was competitive. The inhibition constant (KI) was 20 μg/ml with concentrations of 8 and 40 μg/ml of gentamicin.

  2. 2.

    Experiments with Lysosomes

    Gentamicin and aprotinin (200 μg/ml) activated β-glucuronidase and β-galactosidase from renal lysosomes, but not acid phosphatase. Gentamicin and aprotinin (300 μg/ml) increased the release of acid phosphatase from intact renal lysosomes. Lysosomal degradation of 125I-aprotinin into acid soluble split products was much slower than that of 125I-insulin.

    From our present and previous results it is concluded that binding to the brush border membrane occurs with chemically quite different, however basic drugs and that the number of amino groups per molecule is relevant.

    Nephrotoxicity of aminoglycosides may be related to their endocytic uptake through a direct action on lysosomes.

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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 

  • Canonico, P. G.: Lysosomal catabolism of a protein toxin: staphylococcal enterotoxin B. Biochim. Biophys. Acta 322, 251–257 (1973)

    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., Maunsbach, A. B.: Intralysosomal digestion of lysozyme in renal proximal tubule cells. Kidney Int. 6, 396–407 (1974)

    Google Scholar 

  • Dahlquist, A.: Intestinal disaccharidases. In: Methods in Enzymology, Vol. 8, pp. 584–591. New York: Academic Press 1966

    Google Scholar 

  • Davidson, S. J.: Metal-ion effects on proteolysis and stability in secondary lysosomes of mouse kidney. Biochim. Biophys. Acta 385, 163–172 (1975)

    Google Scholar 

  • Davidson, S. J., Hughes, W. L., Garnwell, A.: Renal protein absorption into sub-cellular particles. I. Studies with intact kidneys and fractionated homogenates. Exp. Cell Res. 67, 171–187 (1971)

    Google Scholar 

  • Elbein, A. D.: Interactions of polynucleotides and other poly-electrolytes with enzymes and other proteins. In: Advances in Enzymology, Vol. 40, pp. 29–64. New York: John Wiley, 1974

    Google Scholar 

  • Falco, F. G., Smith, H. M., Arcieri, G. M.: Nephrotoxicity of aminoglycosides and gentamicin. J. Infect. Dis. 119, 406–409 (1969)

    Google Scholar 

  • Fritz, H., Schult, H., Meister, R., Werle, E.: Herstellung und Eigenschaften von aktiven Derivaten des Trypsin-Kallikrein-Inhibitors aus Rinderorganen. Hoppe-Seylers Z. Physiol. Chem. 350, 1531–1540 (1969a)

    Google Scholar 

  • Fritz, H., Oppitz, K. H., Meckl, D., Kemkes, B., Haendle, H., Schult, H., Werle, E.: Verteilung und Ausscheidung von natürlich vorkommenden und chemisch modifizierten Proteasenin-hibitoren nach intravenöser Injektion bei Ratte, Hund (und Mensch). Hoppe-Seylers Z. Physiol. Chem. 350, 1541–1550 (1969b)

    Google Scholar 

  • Gingell, D.: Membrane permeability change by aggregation of mobile glycoprotein units. J. Theor. Biol. 38, 677–679 (1973)

    Google Scholar 

  • Glossmann, H., Gips, H.: The preparation of brush border membranes from rat kidney using an aqueous two-phase polymer system. Naunyn-Schmiedeberg's Arch. Pharmacol. 282, 439–444 (1974)

    Google Scholar 

  • Harrison, W. O., Silverblatt, F. J., Turck, M.: Gentamicin nephrotoxicity: Failure of three cephalosporins to potentiate injury in rats. Antimicrob. Agents Chemother. 8, 209–215 (1975)

    Google Scholar 

  • Hey, D., Langer, P.: Wirkungen und Nebenwirkungen beim Einsatz von Heparin, Plasmin, Epsilon Aminocapronsäure und Trasylol im Verbrühungsschock. In: Neue Aspekte der Trasylol-Therapie, Vol. 5, pp. 277–290. Stuttgart: Schattauer 1972

    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 

  • Ignarro, L. J.: Effects of antiinflammatory drugs on the stability of rat liver lysosomes in vitro. Biochem. Pharmacol. 20, 2847–2860 (1971)

    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., Erdmann, G., Habermann, E.: The renal handling of polybasic drugs. 1. Gentamicin and aprotinin in intact animals. Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 57–66 (1977)

    Google Scholar 

  • Kosek, J. C., Mazze, R. I., Cousins, M. J.: Nephrotoxicity of gentamicin. Lab. Invest. 30, 48–57 (1974)

    Google Scholar 

  • Kunin, C. M.: Binding of antibiotics to tissue homogenates. J. Infect. Dis. 121, 55–64 (1970)

    Google Scholar 

  • Leseur, J.-P., Fillastre, J.-P., Vaillant, R.: Influence de la gentamicine sur les lysosomes de reins chez le rat. C. R. Acad. Sci. Paris. Serie D, 280, 1693–1696 (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 

  • Lutz, F., Glossmann, H., Frimmer, M.: Binding of 3H-desmethylphalloin to isolated plasma membranes from rat liver. Naunyn-Schmiedeberg's Arch. Pharmacol. 273, 341–351 (1972)

    Google Scholar 

  • Maack, T., Mackensie, D. D. S., Kinter, W. B.: Intracellular pathways of renal reabsorption of lysozyme. Am. J. Physiol. 221, 1609–1616 (1971)

    Google Scholar 

  • Madsen, K., Bode, F., Ottosen, P. D., Baumann, K., Maunsbach, A. G.: Effect of basic amino acids on kidney protein uptake and structure of the proximal tubule. J. Ultrastruct. Res. 57, 221 (1976)

    Google Scholar 

  • Maunsbach, A. B.: Ultrastructure of the proximal tubule. In: Handbook of Physiology, Section 8: Renal Physiology, pp. 31–79. Baltimore: Williams and Wilkins 1973

    Google Scholar 

  • Mogensen, C. E., Vittinghaus, E., Solling, K.: Increased urinary excretion of albumin, light chains, and β2 microglobulin after intravenous arginine administration in normal man. Lancet 1975II, 581–583

  • Norman, S. J., Stone, C. M.: Renal lysosomal catabolism of staphylococcal enterotoxin B. Lab. Invest. 27, 236–241 (1972)

    Google Scholar 

  • Norman, S. J., Jaeger, R. F., Johnsey, R. T.: Pathology of experimental enterotoxemia. The in vivo localization of staphylococcal enterotoxin B. Lab. Invest. 20, 17–25 (1969)

    Google Scholar 

  • Patel, V., Luft, F. C., Yum, M. N., Patel, B., Zeman, W., Kleit, S. A.: Enzymuria in gentamicin-induced kidney damage. Antimicrob. Agents Chemother. 7, 364–369 (1975)

    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 

  • Rübsamen, K., Breithaupt, H., Habermann, E.: Biochemistry and pharmacology of the crotoxin complex. I. Subfractionation and recombination of the crotoxin complex. Naunyn-Schmiedeberg's Arch. Pharmacol. 270, 274–288 (1971)

    Google Scholar 

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

    Google Scholar 

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

    Google Scholar 

  • Stacy, B. D., Wallace, A. L. C., Gemmel, R. T., Wilson, B. W.: Absorption of 125I-labelled sheep growth hormone in single proximal tubules of the rat kidney. J. Endocr. 68, 21–30 (1976)

    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 

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

    Google Scholar 

  • Wahlig, H.: Animal studies on tissue concentrations of gentamicin. 8th Int. Congr. Chemother, Vol. A, 1–74, Athens 1973

  • Wellwood, J. M., Simpson, P. M., Tighe, J. R., Thompson, A. E.: Evidence of gentamicin nephrotoxicity in patients with renal allografts. Brit. Med. J. 3, 278–281 (1975)

    Google Scholar 

  • Wellwood, J. M., Lovell, D., Thompson, A. E., Tighe, J. R.: Renal damage caused by gentamicin. A study of the effects on renal morphology and urinary enzyme excretion. J. Path. 118, 171–182 (1976)

    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 

  • Yuzuriha, T., Katayama, K., Fujita, T.: Studies on biotransformation of lysozyme. II. Tissue distribution of 131I-labeled lysozyme and degradation in kidney after intravenous injection in rats. Chem. Pharm. Bull. 23, 1315–1322 (1975)

    Google Scholar 

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

    Melitta Just & E. Habermann

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  1. Melitta Just
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Just, M., Habermann, E. The renal handling of polybasic drugs. Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 67–76 (1977). https://doi.org/10.1007/BF00505081

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