Pharmacokinetic evaluation of oral dantrolene in the dog

Abstract

The pharmacokinetics of dantrolene and its active metabolite, 5-hydroxydantrolene, after a single oral dose of either 5 mg/kg or 10 mg/kg of dantrolene were 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 hrs, and area under the time-concentration curve (AUC) was 3.87 µg hr/mL. For the 10 mg/kg dose, Cmax was 0.65 µg/ml, t1/2 was 1.21 hrs, and AUC was 5.94 µg hr/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 hrs, 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 µg/mL 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.

Retrospective analysis of hops toxicosis in dogs (2002‐2014): 71 cases

“…After oral administration, dantrolene reaches maximum serum concentrations after 1.26 hours with 10 mg/kg dosing, but peak plasma concentrations are highly variable. 28 This may be a reason for an inadequate response. In addition, some doses were given rectally, and pharmacokinetics of this route in dogs have not been studied.…”

“…IV administration achieves higher serum concentration in a shorter period to resolve MH-related hyperthermia. 28 However, Ratto and Joyner state that "substantial evidence indicating the efficacy of dantrolene for malignant hyperthermia is lacking." 28 The ASPCA-APCC reports a small number of dogs who develop elevations in liver enzymes after the use of dantrolene; therefore, it is recommended that these parameters be monitored after its administration.…”

Effects of oral administration of 5 immunosuppressive agents on activated T‐cell cytokine expression in healthy dogs

“…Four dogs were intact females and 4 were neutered males, with a median age of 2 years (range, 1.3‐7.3 years). Typically, 6‐8 dogs are used for standard pharmacokinetic and pharmacodynamic studies, as described by Riviere, and published by others . Dogs were deemed healthy by detection of no abnormalities on physical examination and a minimum data base (including a complete blood count, serum biochemistry, urinalysis) as well as heartworm testing.…”

Determination and tissue distribution studies of dantrolene sodium with hydroxypropyl‐β‐cyclodextrin in rat tissue by HPLC/MS/MS

“…According to the literature reports, Da has been mainly determined by HPLC (Büyükokuroğlu, 2002;Büyükokuroğlu, Taysi, Polat, & Göçer, 2002;Haraschak et al, 2014). The concentration of Da in rat tissues was determined by HPLC/MS/MS method in this study.…”