Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 2, pp 421–430

Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice

  • Jan H. Beumer
  • Julie L. Eiseman
  • Judith A. Gilbert
  • Julianne L. Holleran
  • Archibong E. Yellow-Duke
  • Dana M. Clausen
  • David Z. D’Argenio
  • Matthew M. Ames
  • Pamela A. Hershberger
  • Robert A. Parise
  • Lihua Bai
  • Joseph M. Covey
  • Merrill J. Egorin
Original Article

DOI: 10.1007/s00280-010-1337-6

Cite this article as:
Beumer, J.H., Eiseman, J.L., Gilbert, J.A. et al. Cancer Chemother Pharmacol (2011) 67: 421. doi:10.1007/s00280-010-1337-6

Abstract

Purpose

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.

Keywords

Tetrahydrouridine THU Bioavailability Metabolism Mouse Cytidine deaminase 

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Jan H. Beumer
    • 1
    • 2
  • Julie L. Eiseman
    • 1
    • 3
  • Judith A. Gilbert
    • 4
  • Julianne L. Holleran
    • 1
  • Archibong E. Yellow-Duke
    • 1
  • Dana M. Clausen
    • 1
  • David Z. D’Argenio
    • 5
  • Matthew M. Ames
    • 4
  • Pamela A. Hershberger
    • 1
    • 3
  • Robert A. Parise
    • 1
    • 2
  • Lihua Bai
    • 1
    • 3
  • Joseph M. Covey
    • 6
  • Merrill J. Egorin
    • 1
    • 3
    • 7
  1. 1.Molecular Therapeutics/Drug Discovery ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  2. 2.Department of Pharmaceutical SciencesUniversity of Pittsburgh School of PharmacyPittsburghUSA
  3. 3.Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Department of Molecular Pharmacology and Experimental TherapeuticsCollege of Medicine, Mayo ClinicRochesterUSA
  5. 5.Department of Biomedical EngineeringUniversity of Southern CaliforniaLos AngelesUSA
  6. 6.Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and DiagnosisNational Cancer InstituteRockvilleUSA
  7. 7.Division of Hematology/Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA

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