Transport and epithelial secretion of the cardiac glycoside, digoxin, by human intestinal epithelial (Caco-2) cells

Br J Pharmacol. 1996 Jul;118(6):1389-96. doi: 10.1111/j.1476-5381.1996.tb15550.x.


1. Human intestinal epithelial Caco-2 cells have been used to investigate the transepithelial permeation of the cardiac glycoside, digoxin. 2. Transepithelial basal to apical [3H]-digoxin flux exceeds apical to basal flux, a net secretion of [3H]-digoxin being observed. At 200 microM digoxin, net secretory flux (Jnet) was 10.8 +/- 0.6 nmol cm-2 h-1. Maximal secretory flux (Jmax) of vinblastine was 1.3 +/- 0.1 nmol cm-2 h-1. Cellular uptake of digoxin was different across apical and basal cell boundaries. It was greatest across the basal surface at 1 microM, whereas at 200 microM, apical uptake exceeded basal uptake. 3. Net secretion of [3H]-digoxin was subject to inhibition by digitoxin and bufalin but was not inhibited by ouabain, convallatoxin, and strophanthidin (all 100 microM). Inhibition was due to both a decrease in Jb-a and an increase in Ja-b. Uptake of [3H]-digoxin at the apical surface was increased by digitoxin and bufalin. All cardiac glycosides decreased [3H]-digoxin uptake at the basal cell surface (except for 100 microM digitoxin). 4. The competitive P-glycoprotein inhibitors, verapamil (100 microM), nifedipine (50 microM) and vinblastine (50 microM) all abolished net secretion of [3H]-digoxin due to both a decrease in Jb-a and an increase in Ja-b. Cellular accumulation of [3H]-digoxin was also increased across both the apical and basal cell surfaces. I-Chloro-2,4,-dinitrobenzene (10 microM), a substrate for glutathione-S-transferase and subsequent ATP-dependent glutathione-S-conjugate secretion, failed to inhibit net secretion of [3H]-digoxin. The increase in absorptive permeability Pa-b (= Ja-b/Ca) and cellular [3H]-digoxin uptake upon P-glycoprotein inhibition, showed that the intestinal epithelium was rendered effectively impermeable by ATP-dependent extrusion at the apical surface. 5. A model for [3H]-digoxin secretion by the intestinal epithelium is likely to involve both diffusional uptake and Na(+)-K+ pump-mediated endocytosis, followed by active extrusion at the apical membrane.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Biological Transport / drug effects
  • Biological Transport / physiology
  • Caco-2 Cells
  • Calcium Channel Blockers / pharmacology
  • Cardiotonic Agents / metabolism*
  • Cardiotonic Agents / pharmacology
  • Digoxin / metabolism*
  • Digoxin / pharmacology
  • Epithelial Cells
  • Epithelium / drug effects
  • Epithelium / metabolism
  • Humans
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Ouabain / pharmacology
  • Potassium / pharmacology
  • Rubidium Radioisotopes
  • Sodium-Potassium-Exchanging ATPase / drug effects
  • Sodium-Potassium-Exchanging ATPase / metabolism


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Calcium Channel Blockers
  • Cardiotonic Agents
  • Rubidium Radioisotopes
  • Ouabain
  • Digoxin
  • Sodium-Potassium-Exchanging ATPase
  • Potassium