title: Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs.
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-1dose was well tolerated. Daily 4 mg kg-1treatment 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-1dose every 21 days was well tolerated. A follow-up dose escalation study is in progress with a lower starting dose.
authors.affiliation: Department of Veterinary Clinical Sciences, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Fulkerson
authors.affiliation: Department of Veterinary Clinical Sciences, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Dhawan
authors.affiliation: Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Center for Cancer Research, Chemical Biology Laboratory, National Cancer Institute, Frederick, MD, USA.
authors.forename: V E
authors.initials: VE
authors.lastname: Marquez
authors.affiliation: Van Adel Research Institute, Grand Rapids, MI, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Jones
authors.affiliation: Department of Environmental Health, School of Public Health, Indiana University, Bloomington, IN, USA.
authors.forename: Z
authors.identifier: http://orcid.org/0000-0003-4189-578X
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Environmental Health, School of Public Health, Indiana University, Bloomington, IN, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Environmental Health, School of Public Health, Indiana University, Bloomington, IN, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Klaunig
authors.affiliation: Department of Veterinary Clinical Sciences, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Fourez
authors.affiliation: Department of Veterinary Clinical Sciences, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Bonney
authors.affiliation: Department of Veterinary Clinical Sciences, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.|Purdue University Center for Cancer Research, West Lafayette, IN, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Knapp
mesh_terms: D000284:Administration, Oral; D042931:Aldehyde Oxidase / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000662:veterinary; D003562:Cytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003600:Cytosol; D019175:DNA Methylation; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D005260:Female; D006207:Half-Life; D007196:Indiana; D008099:Liver / Q000378:metabolism; D018942:Macrolides; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000662:veterinary*; D009503:Neutropenia / Q000139:chemically induced / Q000662:veterinary; D012582:Schools, Veterinary
chemical_list: D018942:Macrolides; C519136:neopeltolide; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside; D042931:Aldehyde Oxidase
keywords: DNA methylation; demethylating agent; dog pharmacokinetics and toxicity; epigeneitcs; zebularine