title: Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice.
abstract: OBJECTIVE
  Cytidine drugs, such as gemcitabine, undergo rapid catabolism and inactivation by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine analogue metabolism. However, THU is only 20% orally bioavailable, which limits its preclinical evaluation and clinical use. Therefore, we characterized THU pharmacokinetics after the administration to mice of the more lipophilic pro-drug triacetyl-THU (taTHU).
  
  
  METHODS
  Mice were dosed with 150 mg/kg taTHU i.v. or p.o. Plasma and urine THU concentrations were quantitated with a validated LC-MS/MS assay. Plasma and urine pharmacokinetic parameters were calculated non-compartmentally and compartmentally.
  
  
  RESULTS
  taTHU did not inhibit CD. THU, after 150 mg/kg taTHU i.v., had a 235-min terminal half-life and produced plasma THU concentrations >1 μg/mL, the concentration shown to inhibit CD, for 10 h. Renal excretion accounted for 40-55% of the i.v. taTHU dose, 6-12% of the p.o. taTHU dose. A two-compartment model of taTHU generating THU fitted the i.v. taTHU data best. taTHU, at 150 mg/kg p.o., produced a concentration versus time profile with a plateau of approximately 10 μg/mL from 0.5-2 h, followed by a decline with a 122-min half-life. Approximately 68% of i.v. taTHU is converted to THU. Approximately 30% of p.o. taTHU reaches the systemic circulation as THU.
  
  
  CONCLUSIONS
  The availability of THU after p.o. taTHU is 30%, when compared to the 20% achieved with p.o. THU. These data will support the clinical studies of taTHU.
authors.affiliation: Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Room G27D, 5117 Centre Avenue, Pittsburgh, PA 5213-1863, USA. beumerjh@upmc.edu
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.forename: Julie L
authors.initials: JL
authors.lastname: Eiseman
authors.forename: Judith A
authors.initials: JA
authors.lastname: Gilbert
authors.forename: Julianne L
authors.initials: JL
authors.lastname: Holleran
authors.forename: Archibong E
authors.initials: AE
authors.lastname: Yellow-Duke
authors.forename: Dana M
authors.initials: DM
authors.lastname: Clausen
authors.forename: David Z
authors.initials: DZ
authors.lastname: D'Argenio
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hershberger
authors.forename: Robert A
authors.initials: RA
authors.lastname: Parise
authors.forename: Lihua
authors.initials: L
authors.lastname: Bai
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Covey
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D019540:Area Under Curve; D055162:Biocatalysis / Q000187:drug effects; D001682:Biological Availability; D001769:Blood / Q000378:metabolism; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013767:Tetrahydrouridine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D014556:Urine / Q000737:chemistry; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D011994:Recombinant Proteins; C557278:triacetyl-3,4,5,6-tetrahydrouridine; D003841:Deoxycytidine; D013767:Tetrahydrouridine; D003564:Cytidine Deaminase; D000093542:Gemcitabine