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Tytuł:
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Evaluation of chronic toxicity of cyclocreatine, a creatine analog, in Sprague Dawley rat after oral gavage administration for up to 26 weeks.
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Autorzy:
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Kale VP; Battelle, Columbus, OH, USA. Electronic address: .
Wallery J; Battelle, Columbus, OH, USA.
Novak J; Battelle, Columbus, OH, USA.
Gibbs S; Battelle, Columbus, OH, USA.
Bourdi M; National Center for Advancing Translational Sciences, National Institute of Health, Bethesda, MD, USA.
Do MT; Lumos Pharma, Austin, TX, USA.
McKew JC; Lumos Pharma, Austin, TX, USA.
Terse PS; National Center for Advancing Translational Sciences, National Institute of Health, Bethesda, MD, USA. Electronic address: .
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Źródło:
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Regulatory toxicology and pharmacology : RTP [Regul Toxicol Pharmacol] 2020 Nov; Vol. 117, pp. 104750. Date of Electronic Publication: 2020 Aug 01.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: <2003>- : Amsterdam : Elsevier
Original Publication: New York : Academic Press, [c1981-
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MeSH Terms:
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Brain/*drug effects
Creatinine/*analogs & derivatives
Toxicity Tests, Chronic/*methods
Administration, Oral ; Animals ; Brain/metabolism ; Brain/pathology ; Creatine/analogs & derivatives ; Creatine/blood ; Creatine/toxicity ; Creatinine/administration & dosage ; Creatinine/blood ; Creatinine/toxicity ; Female ; Male ; Organ Size/drug effects ; Organ Size/physiology ; Rats ; Rats, Sprague-Dawley ; Testis/drug effects ; Testis/metabolism ; Testis/pathology ; Thyroid Gland/drug effects ; Thyroid Gland/metabolism ; Thyroid Gland/pathology ; Time Factors
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Contributed Indexing:
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Keywords: Creatine analog; Creatine transporter deficiency (CTD); Cyclocreatine; LUM-001; Nonclinical safety evaluation; Nonclinical toxicity
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Substance Nomenclature:
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6732XGX1RK (cyclocreatine)
AYI8EX34EU (Creatinine)
MU72812GK0 (Creatine)
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Entry Date(s):
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Date Created: 20200804 Date Completed: 20210708 Latest Revision: 20210708
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Update Code:
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20240105
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DOI:
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10.1016/j.yrtph.2020.104750
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PMID:
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32745584
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Cyclocreatine (LUM-001), a creatine analog, was evaluated for its nonclinical toxicity in Sprague Dawley (SD) rats. Deionized water as a vehicle control article or cyclocreatine was administered by oral gavage twice daily (approximately 12 ± 1 h apart) at 30, 100 and 300 mg/kg/dose levels in rats up to 26 weeks followed by a 28-day recovery period. Due to an increased incidence of seizures, the 600 mg/kg/day dose group males were dosed only for 16-weeks followed by a 14-week recovery period. Thirteen males and four females from 600 mg/kg/day dose group were sacrificed at interim on Day 113 to study plausible brain lesions and not due to moribundity. There was a dose dependent increase in the number of seizure incidences in ≥60 mg/kg/day males and 600 mg/kg/day females. Microscopically, higher incidences of vacuoles in the brain at 600 mg/kg/day in both sexes, thyroid follicular atrophy and follicular cell hypertrophy at ≥200 mg/kg/day in males and 600 mg/kg/day in females, and seminiferous tubular degeneration and/or interstitial edema in testes at ≥200 mg/kg/day were observed. Mean plasma half-life of cyclocreatine was between 3.5 and 6.5 h. In conclusion, chronic administration of cyclocreatine by oral gavage in Sprague Dawley rats induced the seizures and microscopic lesions in the brain, testes and thyroid. Based on the results of this study the highest tested dose of 600 mg/kg/day (mean C max of 151.5 μg/mL; AUC 0-24 of 1970 h*μg/mL) was considered the maximum tolerated dose (MTD) in SD rats.
(Copyright © 2020. Published by Elsevier Inc.)
