Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs
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...
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| Published in: | Veterinary & comparative oncology Vol. 15; no. 1; pp. 226 - 236 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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Oxford, UK
Blackwell Publishing Ltd
01-03-2017
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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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| AbstractList | 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
. Plasma zebularine clearance was constant. Mean maximum concentration (C
) was 23 ± 4.8 and 8.6 ± 1.4 µM following 8 and 4 mg kg
, respectively. Mean half-life was 5.7 ± 0.84 and 7.1 ± 2.1 following 8 and 4 mg kg
, respectively. A single 8 mg kg
dose was well tolerated. Daily 4 mg kg
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
dose every 21 days was well tolerated. A follow-up dose escalation study is in progress with a lower starting dose. 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. M ean maximum concentration (C max ) 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. 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. |
| Author | Fulkerson, C. M. Knapp, D. W. Wu, Q. Fourez, L. M. Jones, P. A. Bonney, P. L. Dhawan, D. Wang, Z. Jones, D. R. Marquez, V. E. Klaunig, J. E. |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26178438$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_3389_fonc_2020_591843 crossref_primary_10_1371_journal_pone_0208709 crossref_primary_10_1155_2017_6589529 crossref_primary_10_1517_14656566_2016_1118053 crossref_primary_10_3390_vetsci9030107 |
| Cites_doi | 10.1038/nrg816 10.1186/s12917-014-0290-8 10.1080/00365520600874198 10.2174/187231208785425818 10.1186/1748-717X-7-39 10.1016/0006-2952(94)90240-2 10.2217/epi.09.44 10.1158/1940-6207.CAPR-07-0008 10.3109/00498258509045354 10.1093/ilar/ilu018 10.1002/cncr.23463 10.1093/jnci/95.5.399 10.1016/j.bbrc.2012.10.143 10.1371/journal.pone.0043720 10.1158/1078-0432.CCR-05-0050 10.1182/blood-2005-05-2033 10.1016/j.juro.2011.09.010 10.1158/1078-0432.CCR-04-2406 10.1016/S0742-8413(00)00095-5 10.1016/j.bcp.2005.04.010 10.1016/0305-0491(74)90256-9 10.1042/BST0320910 10.3390/ph3072022 10.1158/1535-7163.MCT-11-0458 10.1016/j.bmc.2005.07.053 |
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| SubjectTerms | Administration, Oral Aldehyde Oxidase - metabolism Animals Chromatography, High Pressure Liquid - veterinary Cytidine - adverse effects Cytidine - analogs & derivatives Cytidine - pharmacokinetics Cytosol demethylating agent DNA Methylation Dog Diseases - drug therapy dog pharmacokinetics and toxicity Dogs epigeneitcs Female Half-Life Indiana Liver - metabolism Macrolides Male Neoplasms - drug therapy Neoplasms - veterinary Neutropenia - chemically induced Neutropenia - veterinary Schools, Veterinary zebularine |
| Title | Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs |
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