P335 Interactions of FTY720 and FTY720-P with ATP-binding Cassette Transporters

Joy Wang , Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Science, Boston, MA
Eric Sands , BiogenIdec, Cambridge, MA
Cheryl Black , BiogenIdec, Cambridge, MA
David Williams , Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Science, Boston, MA
Monica Chuong , Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Science, Boston, MA
Eman Atef , Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Science, Boston, MA
Barbara LeDuc , Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Science, Boston, MA
Lawrence Gan , BiogenIdec, Cambridge, MA
Guangqing Xiao , BiogenIdec, Cambridge, MA

The immunomodulator pro-drug fingolimod (FTY720) is the first oral drug for relapsing multiple sclerosis, an immune-mediated disease of the CNS.  FTY720 is a structural analogue of sphingosine and is phosphorylated in vivo by sphingosine kinase-2. The phosphorylated FTY720 (FTY720-P) acts as an agonist on four of the five known S1P receptors by triggering a signal to prevent lymphocytes from migrating to sites of inflammation.  While the importance of FTY720 in the immune system and CNS has been established, possible interactions of FTY720 and FTY720-P with CNS drug transporters remain unclear.  In this study, the in vitro interactions of FTY720 and FTY720-P with Multidrug Resistance Proteins (MRPs), P-glycoprotein (P-gp), and Breast Cancer Resistance Protein (BCRP) were investigated using the human primary brain endothelia/astrocyte co-culture model and the Caco-2 cell model. Our results showed that both FTY720 and FTY720-P induced MRP1 gene expression in human brain endothelial cells.  Investigation of similar effects on other transporters expressed in human brain endothelial cells is ongoing.  Furthermore, FTY720 inhibited the transport of digoxin, a reference substrate of P-gp, and estrone-3-sulfate, a reference substrate of BCRP, across Caco-2 monolayer in a dose dependent manner, displaying IC50 values of 35 mM and 51 mM, respectively. The results show that FTY720 and FTY720-P modulate-MRP1 gene expression, thus suggesting they might affect MRP1-mediated drug transport. Whether FTY720 and FTY720-P are substrates of P-gp, BCRP and MRPs is under investigation.