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

Cancer Chemother Pharmacol. 2015 Oct;76(4):803-11. doi: 10.1007/s00280-015-2857-x. Epub 2015 Sep 1.


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.

Trial registration: ClinicalTrials.gov NCT00378807.

Keywords: DNA methylation inhibitor; Fluorodeoxycytidine; Monkeys; Tetrahydrouridine; Toxicity; Toxicokinetics.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Animals
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / blood
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Biological Availability
  • Biotransformation
  • Cohort Studies
  • Cytidine Deaminase / antagonists & inhibitors*
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / blood
  • Deoxycytidine / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacokinetics*
  • Female
  • Half-Life
  • Humans
  • Infusions, Intravenous
  • Macaca fascicularis
  • Male
  • Metabolic Clearance Rate
  • Pilot Projects
  • Tetrahydrouridine / administration & dosage
  • Tetrahydrouridine / blood
  • Tetrahydrouridine / pharmacokinetics*


  • Antimetabolites, Antineoplastic
  • Drug Combinations
  • Enzyme Inhibitors
  • Deoxycytidine
  • Tetrahydrouridine
  • Cytidine Deaminase
  • 5-fluoro-2'-deoxycytidine

Associated data

  • ClinicalTrials.gov/NCT00378807