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Stability of 5-Fluoro-2′-deoxycytidine and Tetrahydrouridine in Combination

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Abstract

In vivo, the DNA methyltransferase inhibitor, 5-fluoro-2′-deoxycytidine (FdCyd, NSC-48006), is rapidly converted to its unwanted metabolites. Tetrahydrouridine (THU, NSC-112907), a cytidine deaminase inhibitor can block the first metabolic step in FdCyd catabolism. Clinical studies have shown that co-administration with THU can inhibit the metabolism of FdCyd. The National Cancer Institute is particularly interested in a 1:5 FdCyd/THU formulation. The purpose of this study was to investigate the in vitro pH stability of FdCyd and THU individually and in combination. A stability-indicating high-performance liquid chromatography method for the quantification of both compounds and their degradants was developed using a ZIC®-HILIC column. The effect of THU and FdCyd on the in vitro degradation of each other was studied as a function of pH from 1.0 to 7.4 in aqueous solutions at 37°C. The degradation of FdCyd appears to be first-order and acid-catalyzed. THU equilibrates with at least one of its degradants. The combination of FdCyd and THU in solution does not affect the stability of either compound. The stability and compatibility of FdCyd and THU in the solid state at increased relative humidity and at various temperatures are also evaluated.

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Acknowledgments

This work was supported by National Cancer Institute under the contract N01-CM-27142.

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Authors and Affiliations

  1. College of Pharmacy, University of Arizona, 1703 East Mabel, Tucson, Arizona, USA

    Duoli Guo, Paul B. Myrdal, Kelly L. Karlage, Sean P. O’Connell, Travis J. Wissinger & Samuel H. Yalkowsky

  2. Pharmaceutical Resources Branch, The National Cancer Institute, Bethesda, Maryland, USA

    S. Esmail Tabibi

Authors
  1. Duoli Guo
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  2. Paul B. Myrdal
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  3. Kelly L. Karlage
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  4. Sean P. O’Connell
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  5. Travis J. Wissinger
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  6. S. Esmail Tabibi
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  7. Samuel H. Yalkowsky
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Correspondence to Duoli Guo.

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Guo, D., Myrdal, P.B., Karlage, K.L. et al. Stability of 5-Fluoro-2′-deoxycytidine and Tetrahydrouridine in Combination. AAPS PharmSciTech 11, 247–252 (2010). https://doi.org/10.1208/s12249-010-9383-2

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  • DOI: https://doi.org/10.1208/s12249-010-9383-2

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