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Epithelial Transport of Anthelmintic Ivermectin in a Novel Model of Isolated Proximal Kidney Tubules

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Abstract

Purpose. The mechanism of excretion of the anthelmintic drug ivermectin was investigated in a novel experimental model of functionally intact proximal tubules isolated from a teleost fish (Fundulus heteroclitus).

Methods. Secretion into the lumens of freshly isolated proximal tubules was studied by means of confocal laser scanning microscopy and digital image analysis using ivermectin and fluorescent labelled ivermectin (BODIPY-ivermectin; BI) as substrates.

Results. The tubular cells rapidly accumulated BI from the medium and attained steady state within 25 minutes. Luminal fluorescence in the steady state was 5-7 times higher as compared to intracellular fluorescence. The secretion of BI into the tubular lumens was inhibited in a dose dependent manner by unlabelled ivermectin and inhibitors of the renal excretory membrane pump p-glycoprotein, namely SDZ PSC-833 and verapamil, but not by leukotriene C4, a substrate of the renal export protein mrp2. Accumulation inside the tubular cells was not affected by the added inhibitors. Ivermectin inhibited the renal secretion of the fluorescent cyclosporin derivative NBDL-CS, a substrate of p-glycoprotein, but not the secretion of the mrp2-substrate fluorescein-methotrexate, nor the secretion of fluorescein, a substrate of the classical renal organic anion transporter.

Conclusions. The data are consistent with BI and ivermectin interacting in teleost kidney tubules exclusively with p-glycoprotein, but not with one of the other known excretory transport systems. In addition, the studies demonstrate that freshly isolated functionally intact kidney tubules from killifish are a useful tool to differentiate the substrate specificity of renal transport systems with respect to drug elimination.

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REFERENCES

  1. M. M. Gottesman and I. Pastan. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62:385–427 (1993).

    Google Scholar 

  2. H. Kusuhara, H. Suzuki, and Y. Sugiyama. The role of p-glycoprotein and a canalicular multispecific organic anion transporter in the hepatobiliary excretion of drugs. J. Pharm. Sci. 87:1025–1040 (1998).

    Google Scholar 

  3. T. Abe, T. Mori, S. Hori, K. Koike, and M. Kuwano. Multidrug resistance protein (MRP). Nippon Rinsho 55:1077–1082 (1997).

    Google Scholar 

  4. M. Müller and P. L. Jansen. Molecular aspects of hepatobiliary transport. Am. J. Physiol. 272:G1285–1303 (1997).

    Google Scholar 

  5. Z. Hollo, L. Homoloya, T. Hegedüs, and B. Sarkadi. Transport properties of the multidrug resistance-associated protein (MRP) in human tumour cells. FEBS Letters 383:99–104 (1996).

    Google Scholar 

  6. J. M. Hougard, P. Poudiiougo, G. Zerbo, R. Meyer, P. Guillet, H. Agoua, A. Seketeli, A. Akboboua, S. Sowah, E. M. Samba, and A. L. Et. Control of onchocerciasis vectors in West Africa: description of the logistics adapted for a large-scale public health program. Sante 4:389–398 (1994).

    Google Scholar 

  7. B. A. Halley, W. J. Vandenheuvel, and P. G. Wislocki. Environmental effects of the usage of avermectins in livestock. Vet. Parasitol. 48:109–125 (1993).

    Google Scholar 

  8. W. C. Campbell and G. W. Benz. Ivermectin: A review of efficiacy and safety. J. Vet. Pharmacol. Ther. 7:1–16 (1984).

    Google Scholar 

  9. A. D. Didier and F. Loor. Decreased biotolerability for ivermectin and cyclosporin A in mice exposed to potent P-glycoprotein inhibitors. Int. J. Cancer 63:263–267 (1995).

    Google Scholar 

  10. G. R. Lankas, M. E. Cartwright, and D. Umbenhauer. P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity. Toxicol. Appl. Pharmacol. 143:357–365 (1997).

    Google Scholar 

  11. J. F. Pouliot, F. L'Heureux, Z. Liu, R. K. Prichard, and E. Georges. Reversal of P-glycoprotein-associated multidrug resistance by ivermectin. Biochem. Pharmacol. 53:17–25 (1997).

    Google Scholar 

  12. A. Didier and F. Loor. The abamectin derivative ivermectin is a potent P-glycoprotein inhibitor. Anticancer Drugs 7:745–751 (1996).

    Google Scholar 

  13. A. H. Schinkel, E. Wagenaar, L. Van Deemter, C. A. Mol, and P. Borst. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J. Clin. Invest. 96:1698–1705 (1995).

    Google Scholar 

  14. A. H. Schinkel, J. J. Smit, O. Van Tellingen, J. H. Beijnen, E. Wagenaar, L. Van Deemter, C. A. Mol, M. A. Van Der Valk, E. C. Robanus Maandag, H. P. Te Riele, and A. L. Et. Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491–502 (1994).

    Google Scholar 

  15. D. S. Miller. Aquatic models for the study of renal transport function and pollutant toxicity. Environ. Health Perspect. 71:59–68 (1987).

    Google Scholar 

  16. J. B. Pritchard, and D. S. Miller. Comparative insights into the mechanisms of renal organic anion and cation secretion. Am. J. Physiol. 261:R1329–R1340 (1991).

    Google Scholar 

  17. U. Schramm, G. Fricker, R. Wenger, and D. S. Miller. p-Glycoprotein mediated transport of a fluorescent cyclosporin analogue in teleost proximal tubules. Am. J. Physiol. 268:F46–F52 (1995).

    Google Scholar 

  18. R. Maasereeuw, F. G. Russel, and D. S. Miller. Multiple pathways of organic anion secretion in renal proximal tubule revealed by confocal microscopy. Am. J. Physiol. 271:F1173–82 (1996).

    Google Scholar 

  19. D. S. Miller, G. Fricker, and J. Drewe. P-glycoprotein-mediated transport of a fluorescent rapamycin derivative in renal proximal tubule. J. Pharmacol. Exp. Ther. 82:440–444 (1997).

    Google Scholar 

  20. R. P. Forster and J. V. Taggart. Use of isolated renal tubules in the estimation of metabolic processes associated with active cellular transport. J. Cell. Comp. Physiol. 36:251–270 (1950).

    Google Scholar 

  21. D. S. Miller and J. B. Pritchard. Indirect coupling of organic anion secretion to sodium in teleost (Paralichthys lethostigma) renal tubules. Am. J. Physiol. 261:R1470–1477 (1991).

    Google Scholar 

  22. L. P. Sullivan, J. A. Grantham, L. Rome, D. Wallace, and J. J. Grantham. Am. J. Physiol. 258:F46–F51 (1990).

    Google Scholar 

  23. D. S. Miller. Daunomycin secretion by killfish renal proximal tubules. Am. J. Physiol. 269:R370–379 (1995).

    Google Scholar 

  24. O. Z. Baraka, B. M. Mahmoud, C. K. Marschke, T. G. Geary, M. M. Homeida, and J. F. Williams. Ivermectin distribution in the plasma and tissues of patiens infected with Onchocerca volvulus. Europ. J. Clin. Pharmacol. 50:407–10 (1996).

    Google Scholar 

  25. E. I. Ette, W. O. A. Thomas, and J. I. Achumba, Ivermectin: a long lasting microfilaricidal agent. DICP 24:426–433 (1990).

    Google Scholar 

  26. M. Xu, M. Molento, W. Blackhall, P. Ribeiro, R. Beech, and R. Prichard. Ivermectin resistance in nematodes may be caused by alteration of P-glycoprotein homolog. Mol. Biochem. Parasitol. 91:327–335 (1998).

    Google Scholar 

  27. Physiology of Fishes. Ed.: David H. Evans, Ph.D., CRC-Press, Boca Raton, New York (1997).

    Google Scholar 

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Authors and Affiliations

  1. Mount Desert Island Biological Laboratory, Salsbury Cove, Maine

    Gert Fricker, Heike Gutmann, Agathe Droulle & David S. Miller

  2. Institute for Pharmaceutical Technology and Biopharmacy, University of Heidelberg, D-69120, Heidelberg, Germany. To whom correspondence should be addressed

    Gert Fricker

  3. Lycee Roosevelt, 51100, Reims, France

    Agathe Droulle

  4. Division of Clinical Pharmacology, Dept. of Internal Medicine and Department of Research, University Clinic (Kantonsspital), Basel, Switzerland

    Heike Gutmann & Jürgen Drewe

  5. National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina

    David S. Miller

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  1. Gert Fricker
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Correspondence to Gert Fricker.

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Fricker, G., Gutmann, H., Droulle, A. et al. Epithelial Transport of Anthelmintic Ivermectin in a Novel Model of Isolated Proximal Kidney Tubules. Pharm Res 16, 1570–1575 (1999). https://doi.org/10.1023/A:1018956621376

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