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.