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Pharmacokinetics, Metabolism, and Oral Bioavailability of the DNA Methyltransferase Inhibitor 5-Fluoro-2'-Deoxycytidine in Mice

Authors' Affiliations: ¹ Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute; Departments of ² Medicine and ³ Pharmacology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and ⁴ Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Toxicology and Pharmacology Branch, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Jan H. Beumer, University of Pittsburgh Cancer Institute, Room G.28, Hillman Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA 15213-1863. Phone: 412-623-3238; Fax: 412-623-1212; E-mail: beumerjh{at}upmc.edu.

Purpose: In vivo, 5-fluoro-2'-deoxycytidine (FdCyd) is rapidly and sequentially converted to 5-fluoro-2'-deoxyuridine, 5-fluorouracil, and 5-fluorouridine. The i.v. combination of FdCyd and 3,4,5,6-tetrahydrouridine (THU), a cytidine deaminase (CD) inhibitor that blocks the first metabolic step in FdCyd catabolism, is being investigated clinically for its ability to inhibit DNA methyltransferase. However, the full effects of THU on FdCyd metabolism and pharmacokinetics are unknown. We aimed to characterize the pharmacokinetics, metabolism, and bioavailability of FdCyd with and without THU in mice.

Experimental Design: We developed a sensitive high-performance liquid chromatography tandem mass spectrometry assay to quantitate FdCyd and metabolites in mouse plasma. Mice were dosed i.v. or p.o. with 25 mg/kg FdCyd with or without coadministration of 100 mg/kg THU p.o. or i.v.

Results: The oral bioavailability of FdCyd alone was 4%. Coadministration with THU increased exposure to FdCyd and decreased exposure to its metabolites; i.v. and p.o. coadministration of THU increased exposure to p.o. FdCyd by 87- and 58-fold, respectively. FdCyd exposure after p.o. FdCyd with p.o. THU was as much as 54% that of i.v. FdCyd with i.v. THU.

Conclusions: FdCyd is well absorbed but undergoes substantial first-pass catabolism by CD to potentially toxic metabolites that do not inhibit DNA methyltransferase. THU is sufficiently bioavailable to reduce the first-pass effect of CD on FdCyd. Oral coadministration of THU and FdCyd is a promising approach that warrants clinical testing because it may allow maintaining effective FdCyd concentrations on a chronic basis, which would be an advantage over other DNA methyltransferase inhibitors that are currently approved or in development.

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				J. H. Beumer, J. L. Eiseman, R. A. Parise, E. Joseph, J. M. Covey, and M. J. Egorin Modulation of Gemcitabine (2',2'-Difluoro-2'-Deoxycytidine) Pharmacokinetics, Metabolism, and Bioavailability in Mice by 3,4,5,6-Tetrahydrouridine Clin. Cancer Res., June 1, 2008; 14(11): 3529 - 3535. [Abstract] [Full Text] [PDF]