Pharmacokinetic evaluation of oral dantrolene in the dog.
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 (Cmax ) was 0.43 μg/mL, terminal half-life (t1/2 ) was 1.26 h, and area under the time-concentration curve (AUC) was 3.87 μg·h/mL. For the 10 mg/kg dose, Cmax was 0.65 μg/mL, t1/2 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: t1/2 , for example, ranged from 0.43 to 6.93 h, Cmax 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.
Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USA.
J L
JL
Haraschak
V C
VC
Langston
R
R
Wang
C
C
Riggs
C
C
Fellman
M K
MK
Ross
C
C
Bulla
K
K
Lunsford
A
A
Mackin
T
T
Archer
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D018592:Cross-Over Studies; D003620:Dantrolene / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004285:Dogs / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006207:Half-Life; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D009125:Muscle Relaxants, Central / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D007376:Interleukin-2; D009125:Muscle Relaxants, Central; D007371:Interferon-gamma; D003620:Dantrolene