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Pharmacokinetic evaluation of oral dantrolene in the dog
Author(s) -
Haraschak J. L.,
Langston V. C.,
Wang R.,
Riggs C.,
Fellman C.,
Ross M. K.,
Bulla C.,
Lunsford K.,
Mackin A.,
Archer T.
Publication year - 2014
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/jvp.12089
Subject(s) - dantrolene , pharmacokinetics , bioavailability , chemistry , pharmacology , oral administration , metabolite , area under the curve , plasma concentration , dosing , medicine , biochemistry , calcium , organic chemistry
The pharmacokinetics of dantrolene and its active metabolite, 5‐hydroxydantrolene, after a single oral dose of either 5 or 10 mg/kg of dantrolene was determined. The effects of exposure to dantrolene and 5‐hydroxydantrolene on activated whole‐blood gene expression of the cytokines interleukin‐2 ( IL ‐2) and interferon‐γ ( IFN ‐γ) were also investigated. When dantrolene was administered at a 5 mg/kg dose, peak plasma concentration ( C max ) was 0.43 μg/mL, terminal half‐life ( t 1/2 ) was 1.26 h, and area under the time–concentration curve ( AUC ) was 3.87 μg·h/mL. For the 10 mg/kg dose, C max was 0.65 μg/mL, t 1/2 was 1.21 h, and AUC was 5.94 μg·h/mL. For all calculated parameters, however, there were large standard deviations and wide ranges noted between and within individual dogs: t 1/2 , for example, ranged from 0.43 to 6.93 h, C max ratios ranged from 1.05 to 3.39, and relative bioavailability ( rF ) values ranged from 0.02 to 1.56. While activated whole‐blood expression of IL ‐2 and IFN ‐γ as measured by qRT ‐ PCR was markedly suppressed following exposure to very high concentrations (30 and 50 μg/mL, respectively) of both dantrolene and 5‐hydroxydantrolene, biologically and therapeutically relevant suppression of cytokine expression did not occur at the much lower drug concentrations achieved with oral dantrolene dosing.