Digoxin Is Not a Substrate for Organic Anion-Transporting Polypeptide Transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but Is a Substrate for a Sodium-Dependent Transporter Expressed in HEK293 Cells

Abstract

ABSTRACT:Digoxin, an orally administered cardiac glycoside cardiovascular drug, has a narrow therapeutic window. Circulating digoxin levels (maximal concentration of ϳ1.5 ng/ml) require careful monitoring, and the potential for drug-drug interactions (DDI) is a concern. Increases in digoxin plasma exposure caused by inhibition of Pglycoprotein (P-gp) have been reported. Digoxin has also been described as a substrate of various organic anion-transporting polypeptide (OATP) transporters, posing a risk that inhibition of OATPs may result in a clinically relevant DDI similar to what has been observed for P-gp. Although studies in rats have shown that Oatps contribute to the disposition of digoxin, the role of OATPs in the disposition of digoxin in humans has not been clearly defined. Using two methods, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, and Solvo observed that digoxin is not a substrate of OATP1A2, OATP1B1, OATP1B3, and OATP2B1. However, digoxin inhibited the uptake of probe substrates of OATP1B1 (IC 50 of 47 M), OATP1B3 (IC 50 > 8.1 M), and OATP2B1 (IC 50 > 300 M), but not OATP1A2 in transfected cell lines. It is interesting to note that digoxin is a substrate of a sodium-dependent transporter endogenously expressed in HEK293 cells because uptake of digoxin was significantly greater in cells incubated with sodium-fortified media compared with incubations conducted in media in which sodium was absent. Thus, although digoxin is not a substrate for the human OATP transporters evaluated in this study, in addition to P-gp-mediated efflux, its uptake and pharmacokinetic disposition may be partially facilitated by a sodium-dependent transporter.

Calorie Restriction Increases P-Glycoprotein and Decreases Intestinal Absorption of Digoxin in Mice

“…Additionally, another advantage of using digoxin is that it is not significantly metabolized in mice (Schinkel et al, 1995Mayer et al, 1997;Kawahara et al, 1999). Although it is possible that digoxin is transported by other transporters (Taub et al, 2011), our observation was that calorie-restricted Abcb1a/b-null mice did not have decreased plasma concentration or increased digoxin content in intestine compared with ad libitum Abcb1a/b-null mice. This suggests that the altered digoxin concentrations observed in calorie-restricted wildtype mice is most likely due to altered P-gp expression.…”

The Janus Kinase 2 Inhibitor Fedratinib Inhibits Thiamine Uptake: A Putative Mechanism for the Onset of Wernicke’s Encephalopathy

“…The uptake experiments in Caco-2 cells were performed 11-17 days after seeding. Cells were incubated with Krebs Henseleit buffer (Taub et al, 2011) (142 mM NaCl, 23.8 mM NaHCO 3 , 4.83 mM KCl, 0.96 mM K 2 HPO 4 , 12.5 mM HEPES, 1.53 mM CaCl 2 , and 1.2 mM MgSO 4 , pH 7.4) containing 15 nM [ 3 H]thiamine at 37°C for 7 minutes in the absence or presence of inhibitors. Unlabeled thiamine, amprolium, and oxythiamine were employed as the positive control inhibitors.…”

Application of Receiver Operating Characteristic Analysis to Refine the Prediction of Potential Digoxin Drug Interactions

“…It was recently demonstrated that digoxin is not a P-gp specific probe substrate but is also a substrate of uptake transporters (Bentz et al, 2005;Kimoto et al, 2011;Taub et al, 2011). These uptake transporters may be present in the experimental systems used to measure IC 50 values.…”

“…These uptake transporters may be present in the experimental systems used to measure IC 50 values. Acharya et al (2008) provided kinetic evidence of an apical and basolateral digoxin uptake transporter in MadinDarby canine kidney (MDCK)II-multidrug resistance protein (MDR1) and Caco-2 cells (A. Lumen and J. Bentz, personal communication), whereas Taub et al (2011) demonstrated active sodium-dependent digoxin uptake in a human embryonic kidney cell line. The in vitro IC 50 values determined in the currently used cell lines with digoxin as a probe substrate may therefore not be entirely attributable to inhibition of P-gp, but may represent inhibition of both P-gp and an uptake transporter.…”