Jack C. Stromatt

Cedazuridine restores oral decitabine bioavailability to intravenous-equivalent levels. A, Plasma concentration–time profiles of decitabine following intravenous or oral (10 mg/kg) administration in WT mice, with or without oral co-administration of oral cedazuridine (3 mg/kg). Cedazuridine markedly increased oral decitabine exposure, restoring systemic exposure to levels comparable with intravenous dosing. B, Plasma concentration–time profiles of decitabine following oral administration (10 mg/kg) in WT vs. CDA-KO mice, with or without oral cedazuridine (3 mg/kg). Cedazuridine co-administration in WT mice mimicked the effect of CDA deletion, producing similar plasma exposures. Data are presented as mean ± SEM (n = 5 mice per group).

Effect of cedazuridine on intravenous decitabine pharmacokinetics in mice.

Cedazuridine increases urinary excretion of decitabine independent of CDA. A, Schematic of experimental design. Mice received oral decitabine (10 mg/kg) with or without oral cedazuridine (3 mg/kg) and were housed in metabolic cages for urine and feces collection. At study endpoint, tissues and excreta were harvested and analyzed for radioactivity to quantify drug distribution and excretion. B, Distribution of total administered decitabine dose across plasma, urine, and feces in WT and CDA-KO mice. In WT animals, co-administration of cedazuridine significantly increased the fraction of decitabine excreted in urine compared with decitabine alone. A similar increase in urinary excretion was observed in CDA-KO mice. Data are presented as mean ± SEM (n = 3 mice per group). ***, P < 0.001; ****, P < 0.0001.

Dose-dependent effects of cedazuridine on oral decitabine pharmacokinetics.

Tissue distribution of radiolabeled decitabine following oral administration.

Plasma concentration–time profiles of decitabine following intravenous or oral administration in wild-type (WT) mice.

Effect of CNT1 deletion on oral decitabine pharmacokinetics.

PK parameters of decitabine in WT, CDA-KO, and CNT1-KO mice following intravenous or oral administration with or without cedazuridine.

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.