Mechanisms Underlying Cedazuridine-Mediated Enhancement of Oral Decitabine Bioavailability.

Decitabine is a DNA hypomethylating agent used in the treatment of patients with myelodysplastic syndromes and acute myeloid leukemia that is administered intravenously because of its poor oral bioavailability. An oral medication containing decitabine and cedazuridine has been approved for human use and has been shown to provide equivalent systemic exposure to decitabine compared with the drug given intravenously. Although the ability of ceduazuridine to boost the oral bioavailability of decitabine has been ascribed to its ability to inhibit first-pass metabolism mediated by cytidine deaminase (CDA), the precise mechanisms underlying this decitabine-cedazuridine interaction remain incompletely understood. We evaluated the pharmacokinetic profile of decitabine in wild-type (WT), CDA-knockout (KO), and concentrative nucleoside transporter 1 (CNT1)-KO mice after oral or intravenous decitabine (10 mg/kg) with or without cedazuridine. The oral bioavailability of decitabine in WT mice was ∼15%, and the area under the curve (AUC) of oral decitabine increased ∼sevenfold in CDA-KO mice and by ∼fivefold in WT mice co-treated with cedazuridine. Cedazuridine also increased the urinary excretion of radiolabeled decitabine from ∼20% to ∼40% of the dose in WT to ∼60% in CDA KO, indicating a CDA-independent mechanism. CNT1-KO mice given decitabine with cedazuridine showed ∼60% lower AUC and ∼1.8-fold higher urinary loss than WT mice. Our results demonstrate that cedazuridine prevents extensive first-pass metabolism of decitabine primarily through CDA inhibition but also enhances renal elimination by affecting CNT1-mediated tubular reabsorption, thereby highlighting renal transport as a source of pharmacokinetic drug-drug interactions with decitabine. SIGNIFICANCE: This study reveals that cedazuridine affects oral decitabine not only by inhibiting CDA metabolism but also by altering CNT1-mediated renal reabsorption. Defining these mechanisms advances understanding of decitabine's pharmacokinetics, explains interpatient variability, and informs safer, more effective use of oral hypomethylating therapy in myeloid malignancies.