Energy-dependent transport of digoxin across renal tubular cell monolayers (LLC-PK1)

Abstract

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.

Relevance of p‐glycoprotein for the enteral absorption of cyclosporin A: in vitro‐in vivo correlation

“…of lipophilic steroids (van Kalken et al, 1993), digoxin (Ito et al, 1993) or colchicine (Speeg & Maldonado, 1994). Therefore, potential overlapping specificities at the p-glycoprotein transport level in epithelial tissues should be considered when cyclosporins are given together with other drugs.…”

Central Nervous System (CNS) Delivery of Glucocorticoids Is Fine-Tuned by Saturable Transporters at the Blood-CNS Barriers and Nonbarrier Regions

“…The half-saturation constant (K m ) for inhibition of mouse oatp2 being 5.7 μ m (21), digoxin is also a substrate of P-gp, the concentration used in these experiments is well above the K m for inhibition of P-gp (14.1 ± 1.6 μ m ) (31). For these studies, n = 10–14 wild-type mice were used for the [ 3 H]cortisol experiments, and n = 14–26 wild-type mice were used for the [ 3 H]corticosterone experiments.…”

In Vivo Probes of Drug Transport: Commonly Used Probe Drugs to Assess Function of Intestinal P-glycoprotein (ABCB1) in Humans

“…Ito et al found that the digoxin transport (200 nM) across renal tubular cells is a saturable (K m ¼ 14.1AE 1.6 mM), energy dependent process, because 2,4-dinitrophenol (1 mM) and sodium azide (10 mM) significantly reduced the b ! a flux (Ito et al 1993a). Moreover, inhibitors of P-glycoprotein (quinidine, verapamil and vincristine) significantly increased the a !…”