title: Oral and intravenous pharmacokinetics of 5-fluoro-2'-deoxycytidine and THU in cynomolgus monkeys and humans.
abstract: BACKGROUND
  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 %).
  
  
  CONCLUSIONS
  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.
authors: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors: Julianne L
authors: JL
authors: Holleran
authors: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA. beumerj@gmail.com.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA. beumerj@gmail.com.|Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA. beumerj@gmail.com.|University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Room G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA. beumerj@gmail.com.
authors: Jan H
authors: JH
authors: Beumer
authors: IIT Research Institute, 10 West 35th Street, Chicago, IL, 60616, USA.
authors: David L
authors: DL
authors: McCormick
authors: IIT Research Institute, 10 West 35th Street, Chicago, IL, 60616, USA.
authors: William D
authors: WD
authors: Johnson
authors: Department of Cancer Biology, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA, 91010, USA.
authors: Edward M
authors: EM
authors: Newman
authors: Division of Cancer Treatment and Diagnosis, NCI, NIH, Bethesda, MD, 20892, USA.
authors: James H
authors: JH
authors: Doroshow
authors: Division of Cancer Treatment and Diagnosis, NCI, NIH, Bethesda, MD, 20892, USA.
authors: Shivaani
authors: S
authors: Kummar
authors: Division of Cancer Treatment and Diagnosis, NCI, NIH, Bethesda, MD, 20892, USA.
authors: Joseph M
authors: JM
authors: Covey
authors: Division of Cancer Treatment and Diagnosis, NCI, NIH, Bethesda, MD, 20892, USA.
authors: Myrtle
authors: M
authors: Davis
authors: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA. eisemanj@upmc.edu.|Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA. eisemanj@upmc.edu.|University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Room G27B, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA. eisemanj@upmc.edu.
authors: Julie L
authors: JL
authors: Eiseman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D001711:Biotransformation; D015331:Cohort Studies; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D010865:Pilot Projects; D013767:Tetrahydrouridine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D003841:Deoxycytidine; D013767:Tetrahydrouridine; D003564:Cytidine Deaminase; C007746:5-fluoro-2'-deoxycytidine
keywords: DNA methylation inhibitor; Fluorodeoxycytidine; Monkeys; Tetrahydrouridine; Toxicity; Toxicokinetics