Stability of 5-fluoro-2′-deoxycytidine and tetrahydrouridine in combination

Duoli Guo, Paul B Myrdal, Kelly L. Karlage, Sean P. O'Connell, Travis J. Wissinger, S. Esmail Tabibi, Samuel H Yalkowsky

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)247-252
Number of pages6
JournalAAPS PharmSciTech
Volume11
Issue number1
DOIs
StatePublished - Mar 2010

Fingerprint

Tetrahydrouridine
Cytidine Deaminase
metabolism
degradation
National Cancer Institute (U.S.)
methyltransferases
Methyltransferases
Humidity
aqueous solutions
clinical trials
relative humidity
high performance liquid chromatography
High Pressure Liquid Chromatography
metabolites
neoplasms
Temperature
Acids
acids
DNA
temperature

Keywords

  • Degradation mechanism
  • FdCyd
  • NSC-112907
  • NSC-48006
  • THU

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Stability of 5-fluoro-2′-deoxycytidine and tetrahydrouridine in combination. / Guo, Duoli; Myrdal, Paul B; Karlage, Kelly L.; O'Connell, Sean P.; Wissinger, Travis J.; Tabibi, S. Esmail; Yalkowsky, Samuel H.

In: AAPS PharmSciTech, Vol. 11, No. 1, 03.2010, p. 247-252.

Research output: Contribution to journalArticle

Guo, Duoli ; Myrdal, Paul B ; Karlage, Kelly L. ; O'Connell, Sean P. ; Wissinger, Travis J. ; Tabibi, S. Esmail ; Yalkowsky, Samuel H. / Stability of 5-fluoro-2′-deoxycytidine and tetrahydrouridine in combination. In: AAPS PharmSciTech. 2010 ; Vol. 11, No. 1. pp. 247-252.
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