ABSTRACT
The aim was to investigate the ability of polysorbate 20 to alter oral digoxin absorption in vitro and drug exposure in vivo via modulation of transporter mediated efflux. Transport studies were performed in MDCKII-MDR1 and Caco-2 cells using 3H-digoxin. Pharmacokinetic studies were performed in wild type and mdr1a deficient Sprague Dawley rats. 3H-digoxin was quantified using liquid scintillation counting. The results showed an increased absorptive transport and a reduced secretory transport in MDCKII-MDR and Caco-2 cells as a function of polysorbate 20 concentrations. The secretory transport (B-A) of digoxin was reduced by 50% at lower polysorbate 20 concentrations than required to increase the absorptive transport (A-B). In vivo, the oral bioavailability of digoxin in wild type animal was increased by 10-25% (w/v) polysorbate 20. In mdr1a deficient Sprague Dawley rats 25% (w/v) polysorbate 20 did not alter the absorption of digoxin after oral administration, but digoxin exposure was significantly different between wild type and mdr1a deficient rats. In conclusion, polysorbate 20 increased absorptive transport across Caco-2 cell monolayers and in vivo in rats in a concentration dependent manner, most likely via inhibition of P-gp rather than through solubilization of digoxin.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/genetics , Digoxin/administration & dosage , Polysorbates/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Administration, Oral , Animals , Biological Availability , Biological Transport , Caco-2 Cells , Digoxin/pharmacokinetics , Dogs , Dose-Response Relationship, Drug , Gene Knockout Techniques , Humans , Madin Darby Canine Kidney Cells , Male , Rats , Rats, Sprague-DawleyABSTRACT
In recent years, our understanding of the importance of membrane transporters (MTs) in the disposition of and response to drugs has increased significantly. MTs are proteins that regulate the transport of endogenous molecules and xenobiotics across the cell membrane. In mammals, two super-families have been identified: ATP-binding cassette (ABC) and solute carrier (SLC) transporters. There is evidence that MTs might mediate polyamines (PA) transport. PA are ubiquitous polycations which are found in all living cells. In mammalian cells, three major PA are synthesised: putrescine, spermidine and spermine; whilst the decarboxylated arginine (agmatine) is not produced by mammals but is synthesised by plants and bacteria. In addition, research in the PA field suggests that PA are transported into cells via a specific transporter, the polyamine transport system(s) (PTS). Although the PTS has not been fully defined, there is evidence that some of the known MTs might be involved in PA transport. In this mini review, eight SLC transporters will be reviewed and their potential to mediate PA transport in human cells discussed. These transporters are SLC22A1, SLC22A2, SLC22A3, SLC47A1, SLC7A1, SLC3A2, SLC12A8A, and SLC22A16. Preliminary data from our laboratory have revealed that SLC22A1 might be involved in the PA uptake; in addition to one member of ABC superfamily (MDR1 protein) might also mediate the efflux of polyamine like molecules.
