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. 2010 Mar;11(1):247-52.
doi: 10.1208/s12249-010-9383-2. Epub 2010 Feb 12.

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

Duoli Guo  1 , Paul B Myrdal, Kelly L Karlage, Sean P O'Connell, Travis J Wissinger, S Esmail Tabibi, Samuel H Yalkowsky
Affiliations

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

Duoli Guo et al. AAPS PharmSciTech. 2010 Mar.

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(R)-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 degrees 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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Figures

Fig. 1
Fig. 1
Chemical structures of FdCyd and THU
Fig. 2
Fig. 2
a Chromatograms of FdCyd and THU in combination at T = 0. b Chromatogram of FdCyd and THU and their degradants after 8 days at pH 2
Fig. 3
Fig. 3
Proposed degradation mechanism of FdCyd
Fig. 4
Fig. 4
Mass spectra of FdCyd (top) and 5-fluorocytosine (bottom)
Fig. 5
Fig. 5
Degradation mechanism of THU
Fig. 6
Fig. 6
Mass spectra of THU (top) and degradant (I) (middle) and degradant (II)
Fig. 7
Fig. 7
a Percentage remaining of FdCyd (in the absence of THU) vs. time. b Percentage remaining of FdCyd (in the presence of THU) vs. time
Fig. 8
Fig. 8
pH-log K obs profile of FdCyd alone and in combination with THU at 37°C
Fig. 9
Fig. 9
a Percentage remaining of THU (in the absence of FdCyd) vs. time. b Percentage remaining of THU (in the presence of FdCyd) vs. time
Fig. 10
Fig. 10
X-ray powder diffraction patterns for a FdCyd and b THU
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