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

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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.

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References

  1. Akaike H (1979) A Bayesian extension of the minimal AIC procedures of autoregressive model fitting. Biometrika 66:237–242

    Article  Google Scholar 

  2. Ashour OM, Naguib FN, el Kouni MH (1996) 5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2′, 3′, 5′-tri-O-acetyluridine, a prodrug of uridine, as modulators of plasma uridine concentration. Implications for chemotherapy. Biochem Pharmacol 51:1601–1611

    Article  CAS  PubMed  Google Scholar 

  3. 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 62:457–464

    Article  CAS  PubMed  Google Scholar 

  4. Beumer JH, Eiseman JL, Parise RA, Joseph E, Covey JM, Egorin MJ (2008) Modulation of gemcitabine (2′, 2′-difluoro-2′-deoxycytidine) pharmacokinetics, metabolism, and bioavailability in mice by 3, 4, 5, 6-tetrahydrouridine. Clin Cancer Res 14:3529–3535

    Article  CAS  PubMed  Google Scholar 

  5. 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 12:7483–7491

    Article  CAS  PubMed  Google Scholar 

  6. 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 62:363–368

    Article  CAS  PubMed  Google Scholar 

  7. Creasey WA, Fink ME, Handschumacher RE, Calabresi P (1963) Clinical and pharmacological studies with 2′, 3′, 5′-triacetyl-6-azauridine. Cancer Res 23:444–453

    CAS  PubMed  Google Scholar 

  8. D’Argenio DZ, Schumitzky A, Wang X (2009) ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los Angeles

  9. Dareer SM, Mulligan LT Jr, White V, Tillery K, Mellett LB, Hill DL (1977) Distribution of [3H]cytosine arabinoside and its products in mice, dogs, and monkeys and effect of tetrahydrouridine. Cancer Treat Rep 61:395–407

    CAS  PubMed  Google Scholar 

  10. Doolittle CH, McDonald CJ, Calabresi P (1977) Pharmacological studies of neurotoxicity in patients with psoriasis treated with azaribine, utilizing high-pressure liquid chromatography. J Lab Clin Med 90:773–785

    CAS  PubMed  Google Scholar 

  11. Doroshow JH, McCoy S, Macdonald JS, Issell BF, Patel T, Cobb PW, Yost KJ, Abbruzzese JL (2006) Phase II trial of PN401, 5-FU, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach: a southwest oncology group study. Invest New Drugs 24:537–542

    Article  CAS  PubMed  Google Scholar 

  12. BRENDA The Comprehensive Enzyme Information System. http://www brenda uni-koeln de/index php4 (2007) Available at http://www.brenda.uni-koeln.de/index.php4 (1/Feb./2007)

  13. el Dareer SM, White V, Chen FP, Mellett LB, Hill DL (1976) Distribution of tetrahydrouridine in experimental animals. Cancer Treat Rep 60:1627–1631

    CAS  PubMed  Google Scholar 

  14. Ellison G, Straumfjord JV Jr, Hummel JP (1958) Buffer capacities of human blood and plasma. Clin Chem 4:452–461

    CAS  PubMed  Google Scholar 

  15. Fenaux P (2005) Inhibitors of DNA methylation: beyond myelodysplastic syndromes. Nat Clin Pract Oncol 2(Suppl 1):S36–S44

    Article  CAS  PubMed  Google Scholar 

  16. Gilbert JA, Salavaggione OE, Ji Y, Pelleymounter LL, Eckloff BW, Wieben ED, Ames MM, Weinshilboum RM (2006) Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res 12:1794–1803

    Article  CAS  PubMed  Google Scholar 

  17. Greer S, Schwade J, Marion HS (1995) Five-chlorodeoxycytidine and biomodulators of its metabolism result in fifty to eighty percent cures of advanced EMT-6 tumors when used with fractionated radiation. Int J Radiat Oncol Biol Phys 32:1059–1069

    Article  CAS  PubMed  Google Scholar 

  18. Hale JT, Bigelow JC, Mathews LA, McCormack JJ (2002) Analytical and pharmacokinetic studies with 5-chloro-2′-deoxycytidine. Biochem Pharmacol 64:1493–1502

    Article  CAS  PubMed  Google Scholar 

  19. Handschumacher RE, Creasey WA, Fink ME, Calabresi P, Welch AD (1962) Pharmacological and clinical studies with triacetyl 6-azauridine. Cancer Chemother Rep 16:267–269

    CAS  PubMed  Google Scholar 

  20. Hidalgo M, Villalona-Calero MA, Eckhardt SG, Drengler RL, Rodriguez G, Hammond LA, Diab SG, Weiss G, Garner AM, Campbell E, Davidson K, Louie A, O’Neil JD, von Borstel R, Von Hoff DD, Rowinsky EK (2000) Phase I and pharmacologic study of PN401 and fluorouracil in patients with advanced solid malignancies. J Clin Oncol 18:167–177

    CAS  PubMed  Google Scholar 

  21. Ho DH, Bodey GP, Hall SW, Benjamin RS, Brown NS, Freireich EJ, Loo TL (1978) Clinical pharmacology of tetrahydrouridine. J Clin Pharmacol 18:259–265

    CAS  PubMed  Google Scholar 

  22. Kaye SB (1998) New antimetabolites in cancer chemotherapy and their clinical impact. Br J Cancer 78(Suppl 3):1–7

    Article  CAS  PubMed  Google Scholar 

  23. Klubes P, Geffen DB, Cysyk RL (1986) Comparison of the bioavailability of uridine in mice after either oral or parenteral administration. Cancer Chemother Pharmacol 17:236–240

    Article  CAS  PubMed  Google Scholar 

  24. Kreis W, Chan K, Budman DR, Schulman P, Allen S, Weiselberg L, Lichtman S, Henderson V, Freeman J, Deere M (1988) Effect of tetrahydrouridine on the clinical pharmacology of 1-beta-D-arabinofuranosylcytosine when both drugs are coinfused over three hours. Cancer Res 48:1337–1342

    CAS  PubMed  Google Scholar 

  25. Kreis W, Woodcock TM, Gordon CS, Krakoff IH (1977) Tetrahydrouridine: physiologic disposition and effect upon deamination of cytosine arabinoside in man. Cancer Treat Rep 61:1347–1353

    CAS  PubMed  Google Scholar 

  26. Lyko F, Brown R (2005) DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J Natl Cancer Inst 97:1498–1506

    Article  CAS  PubMed  Google Scholar 

  27. Marsh JH, Kreis W, Barile B, Akerman S, Schulman P, Allen SL, DeMarco LC, Schuster MW, Budman DR (1993) Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside, tetrahydrouridine, and carboplatin. Cancer Chemother Pharmacol 31:481–484

    Article  CAS  PubMed  Google Scholar 

  28. Mekras JA, Boothman DA, Greer SB (1985) Use of 5-trifluoromethyldeoxycytidine and tetrahydrouridine to circumvent catabolism and exploit high levels of cytidine deaminase in tumors to achieve DNA- and target-directed therapies. Cancer Res 45:5270–5280

    CAS  PubMed  Google Scholar 

  29. Neil GL, Moxley TE, Kuentzel SL, Manak RC, Hanka LJ (1975) Enhancement by tetrahydrouridine (NSC-112907) of the oral activity of 5-azacytidine (NSC-102816) in L1210 leukemic mice. Cancer Chemother Rep 59:459–465

    PubMed  Google Scholar 

  30. Neil GL, Moxley TE, Manak RC (1970) Enhancement by tetrahydrouridine of 1-beta-D-arabinofuranosylcytosine (cytarabine) oral activity in L1210 leukemic mice. Cancer Res 30:2166–2172

    CAS  PubMed  Google Scholar 

  31. Newman EM, Longmate J, Lenz H, Carroll M, Stalter S, Lim D, Raschko D, Shibata S, Somlo G, Doroshow J (2002) Phase I and clinical pharmacokinetic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine: a California Cancer Consortium study. Proceedings of the American Society of Clinical Oncology 21:108a

    Google Scholar 

  32. 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 21:1991–1997

    Article  CAS  PubMed  Google Scholar 

  33. Saif MW, von Borstel R (2006) 5-Fluorouracil dose escalation enabled with PN401 (triacetyluridine): toxicity reduction and increased antitumor activity in mice. Cancer Chemother Pharmacol 58:136–142

    Article  CAS  PubMed  Google Scholar 

  34. Guidance for Industry—Bioanalytical Method Validation (2007) http://www.fda.gov/cder/guidance/index.htm. Accessed May 2001. http://www.fda.gov/cder/guidance/index.htm. Accessed 1 Feb 2007

  35. van Groeningen CJ, Peters GJ, Nadal JC, Laurensse E, Pinedo HM (1991) Clinical and pharmacologic study of orally administered uridine. J Natl Cancer Inst 83:437–441

    Article  PubMed  Google Scholar 

  36. von Borstel R, O’Neil J, Bamat M (2009) Vistonuridine: an orally administered, life-saving antidote for 5-fluorouracil (5FU) overdose. Proc Am Soc Clin Oncol 27:15s

    Google Scholar 

  37. Wong PP, Currie VE, Mackey RW, Krakoff IH, Tan CT, Burchenal JH, Young CW (1979) Phase I evaluation of tetrahydrouridine combined with cytosine arabinoside. Cancer Treat Rep 63:1245–1249

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. B. Rao Vishnuvajjala for his advice, Dr. Richard M. Weinshilboum of Mayo Clinic for recombinant human CD preparation, Diane Mazzei and her colleagues at the University of Pittsburgh Animal Facility for their expert assistance, and the University of Pittsburgh Cancer Institute Hematology/Oncology Writing Group for constructive suggestions regarding the manuscript. This work was supported by contract NO1-CM-52202 and grants P30-CA47904 and P41-EB001978 from the National Cancer Institute. JHB is the recipient of a Hillman Fellows for Innovative Cancer Research Award. MJE is the recipient of an American Society of Clinical Oncology Cancer Foundation Translational Research Professorship.

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Authors and Affiliations

  1. Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Room G27D, 5117 Centre Avenue, Pittsburgh, PA, 5213-1863, USA

    Jan H. Beumer, Julie L. Eiseman, Julianne L. Holleran, Archibong E. Yellow-Duke, Dana M. Clausen, Pamela A. Hershberger, Robert A. Parise, Lihua Bai & Merrill J. Egorin

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

    Jan H. Beumer & Robert A. Parise

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

    Julie L. Eiseman, Pamela A. Hershberger, Lihua Bai & Merrill J. Egorin

  4. Department of Molecular Pharmacology and Experimental Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN, 55905, USA

    Judith A. Gilbert & Matthew M. Ames

  5. Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, 90089, USA

    David Z. D’Argenio

  6. Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20852, USA

    Joseph M. Covey

  7. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Merrill J. Egorin

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  1. Jan H. Beumer
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Correspondence to Jan H. Beumer.

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Beumer, J.H., Eiseman, J.L., Gilbert, J.A. et al. Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice. Cancer Chemother Pharmacol 67, 421–430 (2011). https://doi.org/10.1007/s00280-010-1337-6

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