Role of Organic Anion Transporting Polypeptide 2 in Pharmacokinetics of Digoxin and β-Methyldigoxin in Rats

Funakoshi, Sachiyo; Murakami, Teruo; Yumoto, Ryoko; Kiribayashi, Yoshie; Takano, Mikihisa

doi:10.1002/jps.20346

Cited by 27 publications

(15 citation statements)

References 40 publications

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“…These compounds have low to high clearance values, so while discrepancies in the estimation of extraction ratios may be a contributory factor in the under‐predictions for some of these drugs, other unidentified mechanisms may be more influential, for example active influx or binding to additional tissue constituents. The liver K pu value for the neutral drug digoxin was also significantly under‐predicted by a factor of 22, and in light of the findings of Funakoshi and co‐workers49 the most probable cause is active influx by organic anion transporting polypeptide 2 (oatp2).…”

Section: Discussionmentioning

confidence: 95%

Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions

Rodgers

Rowland

2006

Journal of Pharmaceutical Sciences

795

807

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Section: Discussionmentioning

confidence: 95%

Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions

Rodgers

Rowland

2006

Journal of Pharmaceutical Sciences

795

807

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“…However, because cyclosporine is also an OATP1B3 inhibitor (Smith et al, 2005), it is important to clarify if inhibition of OATP1B3 contributes to the increase in digoxin exposure, in addition to inhibition of P-gp. Likewise, it has been shown in rats that amiodarone can limit the uptake of digoxin into hepatocytes by inhibition of Oatp2, causing an increase in the plasma exposure of digoxin (Funakoshi et al, 2005). The possibility that an amiodarone-digoxin DDI may also occur in humans (i.e., one that may involve P-gp and OATPs) is an issue that requires further study.…”

Section: Introductionmentioning

confidence: 99%

“…In rats, digoxin was reported to be a substrate for Oatp2 and Oatp4 (Cattori et al, 2000;Funakoshi et al, 2005). Digoxin has also been reported to be a substrate for human liver OATP1B3 (Kullak-Ublick et al, 2001) and kidney OATP4C1 (Mikkaichi et al, 2004;Chu et al, 2007) on the basis of studies conducted using recombinant expression systems.…”

Section: Introductionmentioning

confidence: 99%

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

Taub¹,

Mease²,

Sane³

et al. 2011

Drug Metab Dispos

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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.

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“…Both Noé et al23 and Funakoshi et al24 reported that digoxin is a substrate of OATP2. Considering the structures of digoxin and periplocin are similar, we assume that the periplocin may also be transported by OATP2.…”

Section: Resultsmentioning

confidence: 99%

P-glycoprotein- and organic anion-transporting polypeptide-mediated transport of periplocin may lead to drug–herb/drug–drug interactions

Liang¹,

Deng²,

Xing³

et al. 2014

DDDT

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Periplocin, an active and toxic component of the traditional Chinese herbal medicine Periploca sepium Bge, is a cardiac glycoside compound that has been implicated in various clinical accidents. This study investigated the role of transporters in the intestinal absorption and biliary excretion of periplocin, as well as the possible metabolic mechanism of periplocin in liver S9. In a bidirectional transport assay using Madin–Darby canine kidney (MDCK) and MDCK multidrug-resistance protein (MRP)-1 cell monolayers, both in situ intestinal and liver-perfusion models were used to evaluate the role of efflux and uptake transporters on the absorption and biliary excretion of periplocin. In addition, in vitro metabolism of periplocin was investigated by incubating with human/rat liver S9 homogenate fractions to evaluate its metabolic mechanisms in liver metabolic enzymes. The results showed that P-glycoprotein (P-gp) was involved in the intestinal absorption of periplocin, whereas MRP2 and breast cancer-resistance protein were not. The efflux function of P-gp may be partly responsible for the low permeability and bioavailability of periplocin. Moreover, both inhibitors of P-gp and organic anion-transporting polypeptides (OATPs) increased periplocin biliary excretion. No obvious indications of metabolism were observed in the in vitro incubation system, which suggests that periplocin did not interact with the hepatic drug metabolic enzymes. The results of this study showed that the efflux and uptake transporters P-gp and OATPs were involved in the absorption and biliary excretion of periplocin, which may partially account for its low permeability and bioavailability. As a toxic compound, potential drug–herb/herb–herb interactions based on OATPs and P-gp should be taken into account when using P. sepium Bge in the clinic.

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Role of Organic Anion Transporting Polypeptide 2 in Pharmacokinetics of Digoxin and β-Methyldigoxin in Rats

Cited by 27 publications

References 40 publications

Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions

Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions

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

P-glycoprotein- and organic anion-transporting polypeptide-mediated transport of periplocin may lead to drug–herb/drug–drug interactions

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Role of Organic Anion Transporting Polypeptide 2 in Pharmacokinetics of Digoxin and β-Methyldigoxin in Rats

Cited by 27 publications

References 40 publications

Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions

Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions

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

P-glycoprotein- and organic anion-transporting polypeptide-mediated transport of periplocin may lead to drug&ndash;herb/drug&ndash;drug interactions

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P-glycoprotein- and organic anion-transporting polypeptide-mediated transport of periplocin may lead to drug–herb/drug–drug interactions