%0 Journal Article %A Marilyn Giacomini %A Jia Hao %A Xiaomin Liang %A Jayaraman Chandrasekhar %A Jolyn Twelves %A J Andrew Whitney %A Eve-Irene Lepist %A Adrian S Ray %T Interaction of 2,4-Diaminopyrimidine Containing Drugs Including Fedratinib and Trimethoprim with Thiamine Transporters %D 2016 %R 10.1124/dmd.116.073338 %J Drug Metabolism and Disposition %P dmd.116.073338 %X Inhibition of thiamine transporters has been proposed as a putative mechanism for the observation of Wernicke’s encephalopathy and subsequent termination of clinical development of fedratinib, a Janus Kinase inhibitor (JAKi). This study aimed to determine the potential for other JAKi to inhibit thiamine transport using Caco-2 and thiamine transporter (THTR) over-expressing cells and to better elucidate the structural basis for interacting with THTR. Only JAKi containing a 2,4-diaminopyrimidine were observed to inhibit thiamine transporters. Fedratinib inhibited thiamine uptake into Caco-2 cells (IC50 = 0.940 µM) and THTR-2 (IC50 = 1.36 µM) and, to a lesser extent, THTR-1 (IC50 = 7.10 µM) over-expressing cells. Two other JAKi containing this moiety, AZD1480 and cerdulatinib, were weaker inhibitors of the thiamine transporters. Other JAKi—including monoaminopyrimidines, such as momelotinib, and non-aminopyrimidines, such as filgotinib—did not have any inhibitory effects on thiamine transport. A pharmacophore model derived from the minimized structure of thiamine suggests that 2,4-diaminopyrimidine–containing compounds can adopt a conformation matching several key features of thiamine. Further studies with drugs containing a 2,4-diaminopyrimidine resulted in the discovery that the antibiotic trimethoprim also potently inhibits THTR-1 (IC50 = 6.84 µM) and THTR-2 (IC50 = 5.56 µM)-mediated thiamine uptake. Fedratinib and trimethoprim were also found to be substrates for THTR; a finding with important implications for their disposition in the body. In summary, our results show that not all JAKi have the potential to inhibit thiamine transport and further establish the interaction of these transporters with xenobiotics. %U https://dmd.aspetjournals.org/content/dmd/early/2016/10/28/dmd.116.073338.full.pdf