In vitro drug-drug interactions of decitabine and tetrahydrouridine involving drug transporters and drug metabolising enzymes

1. NDec is a novel, oral, fixed-dose formulation of decitabine and tetrahydrouridine that is currently being developed for the treatment of patients with sickle cell disease. Here, we examine the potential for both components of NDec to interact with key drug metabolising enzymes (tetrahydrouridine only) and drug transporters (decitabine and tetrahydrouridine). 2. This study assessed the inhibition and induction of cytochrome P450 (CYP) enzymes by tetrahydrouridine, as well as the involvement of specific drug metabolising enzymes in tetrahydrouridine metabolism. Inhibition of efflux and uptake transporters by both decitabine and tetrahydrouridine was also studied. 3. Tetrahydrouridine did not inhibit or induce relevant CYP enzymes at concentrations ranging from 0.1 to 100 mu M. Metabolism of tetrahydrouridine did not occur in the presence of the human drug metabolising enzymes tested. Tetrahydrouridine showed weak inhibition towards the MATE2-K transporter (similar to 30% inhibition at 5 and 50 mu M), which was not deemed clinically relevant. Tetrahydrouridine did not inhibit any of the remaining uptake or efflux transporters. Decitabine (0.5 and 5 mu M) did not inhibit any of the evaluated uptake or efflux drug transporters. 4. Data presented confirm that tetrahydrouridine and decitabine are unlikely to be involved in metabolism- or transporter-based drug-drug interactions.