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 due to 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 remains 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 was increased ~7-fold in CDA-KO mice and by ~5-fold 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.