Tetrahydrouridine pretreatment increases tissue exposure of ¹⁴ C-decitabine in mice

Decitabine (DEC) is rapidly deaminated by cytidine deaminase (CDA); tetrahydrouridine (THU), a CDA inhibitor, reduces degradation and increases DEC exposure. This is clinically relevant in sickle cell disease (SCD), where DEC increases foetal haemoglobin in erythrocytes.The effect of THU pre-treatment on the tissue distribution of radiolabelled decitabine ([14C]-DEC) was studied in mouse by quantitative whole-body autoradiography and area under the concentration curve (AUC) as exposure metric.The decitabine-related exposure was highest in haematolymphoid tissues, particularly the bone marrow, followed by gastrointestinal tissues across all dosing groups, with up to 115‑ and 18‑fold higher levels than in blood, respectively.Furthermore, THU pre-treatment increased the exposure in haematolymphoid tissues, gastrointestinal tract, and reproductive organs by up to 4.8-, 6.2-, and 5.3-fold, respectively.In conclusion, THU pre-treatment enhances decitabine-related exposure in target tissues like bone marrow, supporting pre-dosing of THU prior to DEC treatment of SCD.