Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs

C. M. Fulkerson, D. Dhawan, D. R. Jones, V. E. Marquez, P. A. Jones, Z. Wang, Q. Wu, J. E. Klaunig, L. M. Fourez, P. L. Bonney, D. W. Knapp

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The purpose of this study was to determine the plasma pharmacokinetics (PK) and toxicity of zebularine, an oral cytidine analog with demethylating activity, in dogs. Plasma zebularine concentrations were determined by HPLC-MS/MS following an oral zebularine dose of 8 or 4 mg kg−1. Plasma zebularine clearance was constant. Mean maximum concentration (Cmax) was 23 ± 4.8 and 8.6 ± 1.4 µM following 8 and 4 mg kg−1, respectively. Mean half-life was 5.7 ± 0.84 and 7.1 ± 2.1 following 8 and 4 mg kg−1, respectively. A single 8 mg kg−1 dose was well tolerated. Daily 4 mg kg−1 treatment in three laboratory dogs resulted in grade 4 neutropenia (n = 3), grade 1 anorexia (n = 2) and grade 1 or 2 dermatologic changes (n = 2). All adverse events resolved with supportive care. A 4 mg kg−1 dose every 21 days was well tolerated. A follow-up dose escalation study is in progress with a lower starting dose.

Original languageEnglish (US)
Pages (from-to)226-236
Number of pages11
JournalVeterinary and Comparative Oncology
Volume15
Issue number1
DOIs
StatePublished - Mar 1 2017

Keywords

  • DNA methylation
  • demethylating agent
  • dog pharmacokinetics and toxicity
  • epigeneitcs
  • zebularine

ASJC Scopus subject areas

  • veterinary(all)

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    Fulkerson, C. M., Dhawan, D., Jones, D. R., Marquez, V. E., Jones, P. A., Wang, Z., Wu, Q., Klaunig, J. E., Fourez, L. M., Bonney, P. L., & Knapp, D. W. (2017). Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs. Veterinary and Comparative Oncology, 15(1), 226-236. https://doi.org/10.1111/vco.12159