Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Mekras JA, Boothman DA, Perez LM, Greer S (1984) Use of 5-fluorodeoxycytidine and tetrahydrouridine to exploit high levels of deoxycytidylate deaminase in tumors to achieve DNA- and target-directed therapies. Cancer Res 44(6):2551–2560

    CAS  PubMed  Google Scholar 

  2. Boothman DA, Briggle TV, Greer S (1987) Tumor-selective metabolism of 5-fluoro-2’-deoxycytidine coadministered with tetrahydrouridine compared to 5-fluorouracil in mice bearing Lewis lung carcinoma. Cancer Res 47(9):2354–2362

    CAS  PubMed  Google Scholar 

  3. Boothman DA, Briggle TV, Greer S (1987) Protective, tumor-selective dual pathway activation of 5-fluoro-2’-deoxycytidine provided by tetrahydrouridine in mice bearing mammary adenocarcinoma-755. Cancer Res 47(9):2344–2353

    CAS  PubMed  Google Scholar 

  4. Kaysen J, Spriggs D, Kufe D (1986) Incorporation of 5-fluorodeoxycytidine and metabolites into nucleic acids of human MCF-7 breast carcinoma cells. Cancer Res 46(9):4534–4538

    CAS  PubMed  Google Scholar 

  5. Smith SS, Kaplan BE, Sowers LC, Newman EM (1992) Mechanism of human methyl-directed DNA methyltransferase and the fidelity of cytosine methylation. Proc Natl Acad Sci USA 89(10):4744–4748

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Chuang JC, Yoo CB, Kwan JM, Li TW, Liang G, Yang AS, Jones PA (2005) Comparison of biological effects of non-nucleoside DNA methylation inhibitors versus 5-aza-2’-deoxycytidine. Mol Cancer Ther 4(10):1515–1520. doi:10.1158/1535-7163.MCT-05-0172

    Article  CAS  PubMed  Google Scholar 

  7. Beumer JH, Eiseman JL, Parise RA, Joseph E, Holleran JL, Covey JM, Egorin MJ (2006) Pharmacokinetics, metabolism, and oral bioavailability of the DNA methyltransferase inhibitor 5-fluoro-2’-deoxycytidine in mice. Clin Cancer Res Off J Am Assoc Cancer Res 12(24):7483–7491. doi:10.1158/1078-0432.CCR-06-1250

    Article  CAS  Google Scholar 

  8. Kinders RJ, Wang L, Kummar S, Khin S, Balasubramanian P, Zhu W, Parchment RE, Newman E, Tomaszewski JE, Doroshow JH (2011) Abstract A106: Investigation of 5-fluorodeoxycytidine with tetrahydrouracil as a demethylation regimen in solid tumors. Mol Cancer Ther 10(Suppl 1):A106–A106. doi:10.1158/1535-7163.targ-11-a106

    Article  Google Scholar 

  9. Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, Klimek V, Slack J, de Castro C, Ravandi F, Helmer R 3rd, Shen L, Nimer SD, Leavitt R, Raza A, Saba H (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106(8):1794–1803. doi:10.1002/cncr.21792

    Article  CAS  PubMed  Google Scholar 

  10. Quintas-Cardama A, Santos FP, Garcia-Manero G (2010) Therapy with azanucleosides for myelodysplastic syndromes. Nature Rev Clin Oncol 7(8):433–444. doi:10.1038/nrclinonc.2010.87

    Article  CAS  Google Scholar 

  11. Newman EM, Morgan RJ, Kummar S, Beumer JH, Blanchard MS, Ruel C, El-Khoueiry AB, Carroll MI, Hou JM, Li C, Lenz HJ, Eiseman JL, Doroshow JH (2015) A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2’-deoxycytidine, administered with tetrahydrouridine. Cancer Chemother Pharmacol 75(3):537–546. doi:10.1007/s00280-014-2674-7

    Article  CAS  PubMed  Google Scholar 

  12. Beumer JH, Parise RA, Newman EM, Doroshow JH, Synold TW, Lenz HJ, Egorin MJ (2008) Concentrations of the DNA methyltransferase inhibitor 5-fluoro-2’-deoxycytidine (FdCyd) and its cytotoxic metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU). Cancer Chemother Pharmacol 62(2):363–368. doi:10.1007/s00280-007-0603-8

    Article  CAS  PubMed  Google Scholar 

  13. Beumer JH, Eiseman JL, Parise RA, Florian JA Jr, Joseph E, D’Argenio DZ, Parker RS, Kay B, Covey JM, Egorin MJ (2008) Plasma pharmacokinetics and oral bioavailability of 3,4,5,6-tetrahydrouridine, a cytidine deaminase inhibitor, in mice. Cancer Chemother Pharmacol 62(3):457–464. doi:10.1007/s00280-007-0625-2

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Parise RA, Egorin MJ, Eiseman JL, Joseph E, Covey JM, Beumer JH (2007) Quantitative determination of the cytidine deaminase inhibitor tetrahydrouridine (THU) in mouse plasma by liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 21(13):1991–1997. doi:10.1002/rcm.3054

    Article  CAS  PubMed  Google Scholar 

  15. Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Reports Part 1 50 (4):219–244

  16. De Verdier CH, Potter VR (1960) Alternative pathways of thymine and uracil metabolism in the liver and hepatoma. J Natl Cancer Inst 24:13–29

    Google Scholar 

  17. Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S (2008) A pilot pharmacokinetic study of oral azacitidine. Leukemia 22(9):1680–1684. doi:10.1038/leu.2008.145

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Funding for these studies was provided by NCI contracts N01-CM-42202 (IIT Research Institute), N01-CM-52202, N01CM-2011-0015, UM1CA186690 (University of Pittsburgh), and UM1CA186717 (City of Hope). This project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30CA047904. The authors would like to thank the Merrill Egorin Writing Group at UPCI for careful review of this manuscript.

Author information

Authors and Affiliations

  1. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Julianne L. Holleran, Jan H. Beumer & Julie L. Eiseman

  2. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Jan H. Beumer

  3. Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Jan H. Beumer

  4. IIT Research Institute, 10 West 35th Street, Chicago, IL, 60616, USA

    David L. McCormick & William D. Johnson

  5. Department of Cancer Biology, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA, 91010, USA

    Edward M. Newman

  6. Division of Cancer Treatment and Diagnosis, NCI, NIH, Bethesda, MD, 20892, USA

    James H. Doroshow, Shivaani Kummar, Joseph M. Covey & Myrtle Davis

  7. Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Julie L. Eiseman

  8. University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Room G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA

    Jan H. Beumer

  9. University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Room G27B, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA

    Julie L. Eiseman

Authors
  1. Julianne L. Holleran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan H. Beumer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David L. McCormick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William D. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edward M. Newman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. James H. Doroshow
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shivaani Kummar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joseph M. Covey
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Myrtle Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Julie L. Eiseman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jan H. Beumer or Julie L. Eiseman.

Ethics declarations

Conflict of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Holleran, J.L., Beumer, J.H., McCormick, D.L. et al. Oral and intravenous pharmacokinetics of 5-fluoro-2′-deoxycytidine and THU in cynomolgus monkeys and humans. Cancer Chemother Pharmacol 76, 803–811 (2015). https://doi.org/10.1007/s00280-015-2857-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-015-2857-x

Keywords

Search

Navigation