Energy-dependent transport of digoxin across renal tubular cell monolayers (LLC-PK1).
Digoxin secretory transport across renal tubular cell monolayers (LLC-PK1) grown on permeable filters was characterized. Metabolic inhibitors reduced total and specific basolateral to apical (B-A) flux of digoxin and conversely increased the apical to basolateral (A-B) flux. The specific transport of digoxin from the basolateral to the apical compartment was saturable, with a maximum velocity of transport of 184.5 +/- 38.0 pmol.cm-2.h-1 and a Michaelis-Menten constant (Km) of 14.1 +/- 1.6 microM. In addition, B-A flux of digoxin resulted in accumulation of digoxin in the apical compartment against the concentration gradient. P-Glycoprotein inhibitors such as quinidine, verapamil, vincristine, and cyclosporine increased the net A-B flux and inhibited the total B-A flux without affecting the nonspecific flux significantly. Tetraethylammonium, a prototype substrate for an organic cation transport system, had no such effect. Our results suggest that digoxin undergoes transepithelial secretion by an energy-dependent, carrier-mediated process in renal tubules, a process that seems to be distinct from the tetraethylammonium transport system.
Ito
S
S
Department of Paediatrics and Pharmacology, Research Institute, Hospital for Sick Children, Toronto, Ont., Canada.
Koren
G
G
Harper
P A
PA
Silverman
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004077:Digoxin / Q000493:pharmacokinetics*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D013552:Swine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000963:Antimetabolites; D001798:Blood Proteins; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D004077:Digoxin