Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs |
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| Authors: | 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 |
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| Institution: | 1. Department of Veterinary Clinical Sciences, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA;2. Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA;3. Center for Cancer Research, Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA;4. Van Adel Research Institute, Grand Rapids, MI, USA;5. Department of Environmental Health, School of Public Health, Indiana University, Bloomington, IN, USA;6. Purdue University Center for Cancer Research, West Lafayette, IN, USA |
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| 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. |
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| Keywords: | demethylating agent DNA methylation dog pharmacokinetics and toxicity epigeneitcs zebularine |
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