Abstract
Digoxin, an orally administered cardiac glycoside cardiovascular drug, has a narrow therapeutic window. Circulating digoxin levels (maximal concentration of ∼1.5 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 P-glycoprotein (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 (IC50 of 47 μM), OATP1B3 (IC50 > 8.1 μM), and OATP2B1 (IC50 > 300 μM), 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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040816.
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ABBREVIATIONS:
- DDIs
- drug interactions
- OATP
- organic anion-transporting polypeptide
- P-gp
- P-glycoprotein
- BI
- Boehringer Ingelheim
- GSK
- GlaxoSmithKline
- DMEM
- Dulbecco's modified Eagle's medium
- FBS
- fetal bovine serum
- HBSS
- Hanks' balanced salt solution
- DPBS
- Dulbecco's phosphate-buffered saline
- WT
- wild type
- HEK
- human embryonic kidney
- CHO
- Chinese hamster ovary
- MDCK
- Madin-Darby canine kidney
- MRP
- multidrug resistance-associated protein
- ASBT
- apical sodium-dependent bile acid transporter
- SMVT
- sodium-dependent multivitamin transporter
- SCHH
- sandwich-cultured human hepatocytes
- OSTα
- organic solute transporter-α
- OSTβ
- organic solute transporter-β
- LY335979
- (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo(a,e)cyclopropa(c)cycloheptan-6-yl)-α-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride.
- Received May 19, 2011.
- Accepted August 16, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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