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A Mass Balance and Disposition Study of the DNA Methyltransferase Inhibitor Zebularine (NSC 309132) and Three of Its Metabolites in Mice

Authors' Affiliations: ¹ Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute and Departments of ² Medicine and ³ Pharmacology, School of Medicine and ⁴ Department of Chemical and Petroleum Engineering, School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania; ⁵ Biomedical Engineering, University of Southern California, Los Angeles, California; and ⁶ Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Jan H. Beumer, University of Pittsburgh Cancer Institute, Room G.28, Hillman Research Pavilion, 5117 Centre Avenue Pittsburgh, PA 15213-1863. Phone: 412-623-3238; Fax: 412-623-1212; E-mail: beumerjh{at}upmc.edu.

Purpose: To elucidate the in vivo metabolic fate of zebularine (NSC 309132), a DNA methyltransferase inhibitor proposed for clinical evaluation in the treatment of cancer.

Experimental Design: Male, CD₂F₁ mice were dosed i.v. with 100 mg/kg 2-[¹⁴C]zebularine. At specified times between 5 and 1,440 minutes, mice were euthanized. Plasma, organs, carcass, urine, and feces were collected and assayed for total radioactivity. Plasma and urine were also analyzed for zebularine and its metabolites with a previously validated high-pressure liquid chromatography assay. A similar experiment was done with 2-[¹⁴C]uridine, the proposed primary metabolite of zebularine.

Results: Maximum plasma concentrations were 462, 306, 33.6, 21.7, and 11.5 µmol/L for total radioactivity, zebularine, uridine, uracil (each at 5 minutes), and dihydrouracil (at 15 minutes), respectively. Total radioactivity, zebularine, uridine, uracil, and dihydrouracil were rapidly eliminated from plasma, and after 45 minutes, none of the individual compounds could be quantitated by high-pressure liquid chromatography. Plasma data were consistent with sequential conversion of zebularine to uridine, uracil, and dihydrouracil. 2-Pyrimidinone was not observed. Prolonged retention of radioactivity, at concentrations higher than in plasma, was observed in tissues. Recovery of given radioactivity in urine (30.3% of dose), feces (0.4% of dose), cage wash (7.9% of dose), and tissues and carcass (6.1% of dose) after 24 hours implied that up to 55% of radioactivity was expired as ¹⁴CO₂. Comparison of zebularine and uridine pharmacokinetic data indicated that 40% of the zebularine dose was converted to uridine.

Conclusions: Zebularine is extensively and rapidly metabolized into endogenous compounds that are unlikely to have effects at the concentrations observed.

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