Oral and intravenous pharmacokinetics of 5-fluoro-2′-deoxycytidine and THU in cynomolgus monkeys and humans

Julianne L. Holleran, Jan H. Beumer, David L. McCormick, William D. Johnson, Edward M. Newman, James H. Doroshow, Shivaani Kummar, Joseph M. Covey, Myrtle Davis, Julie L. Eiseman

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Introduction: 5-Fluoro-2′-deoxycytidine (FdCyd; NSC48006), a fluoropyrimidine nucleoside inhibitor of DNA methylation, is degraded by cytidine deaminase (CD). Pharmacokinetic evaluation was carried out in cynomolgus monkeys in support of an ongoing phase I study of the PO combination of FdCyd and the CD inhibitor tetrahydrouridine (THU; NSC112907). Methods: Animals were dosed intravenously (IV) or per os (PO). Plasma samples were analyzed by LC-MS/MS for FdCyd, metabolites, and THU. Clinical chemistry and hematology were performed at various times after dosing. A pilot pharmacokinetic study was performed in humans to assess FdCyd bioavailability. Results: After IV FdCyd and THU administration, FdCyd C max and AUC increased with dose. FdCyd half-life ranged between 22 and 56 min, and clearance was approximately 15 mL/min/kg. FdCyd PO bioavailability after THU ranged between 9 and 25 % and increased with increasing THU dose. PO bioavailability of THU was less than 5 %, but did result in plasma concentrations associated with inhibition of its target CD. Human pilot studies showed comparable bioavailability for FdCyd (10 %) and THU (4.1 %). Conclusion: Administration of THU with FdCyd increased the exposure to FdCyd and improved PO FdCyd bioavailability from <1 to 24 %. Concentrations of THU and FdCyd achieved after PO administration are associated with CD inhibition and hypomethylation, respectively. The schedule currently studied in phase I studies of PO FdCyd and THU is daily times three at the beginning of the first and second weeks of a 28-day cycle.

Original languageEnglish (US)
Pages (from-to)803-811
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Issue number4
StatePublished - Oct 22 2015
Externally publishedYes


  • DNA methylation inhibitor
  • Fluorodeoxycytidine
  • Monkeys
  • Tetrahydrouridine
  • Toxicity
  • Toxicokinetics

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)


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