Epithelial transport of anthelmintic ivermectin in a novel model of isolated proximal kidney tubules

Pharm Res. 1999 Oct;16(10):1570-5. doi: 10.1023/a:1018956621376.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / pharmacology
  • Animals
  • Anthelmintics / pharmacokinetics*
  • Biological Transport, Active
  • Calcium Channel Blockers / pharmacology
  • Chemokines, CC
  • Cyclosporins / pharmacology
  • Cytokines / metabolism
  • Epithelium / metabolism
  • In Vitro Techniques
  • Ivermectin / pharmacokinetics*
  • Kidney Tubules, Proximal / metabolism*
  • Killifishes / metabolism*
  • Macrophage Inflammatory Proteins*
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Verapamil / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anthelmintics
  • Calcium Channel Blockers
  • Ccl9 protein, mouse
  • Chemokines, CC
  • Cyclosporins
  • Cytokines
  • Macrophage Inflammatory Proteins
  • Ivermectin
  • Verapamil
  • valspodar