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

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Abstract
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 μm 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 μm, whereas at 200 μm, 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 μm). 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 μm digitoxin). 4 The competitive P-glycoprotein inhibitors, verapamil (100 μm), nifedipine (50 μm) and vinblastine (50 μm) 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. 1-Chloro-2,4,-dinitrobenzene (10 μm), 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.

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