Pharmacokinetics and metabolism of dantrolene in horses

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Abstract

Dantrolene is a skeletal muscle relaxant used commonly in performance horses to prevent exertional rhabdomyolysis. The goal of the study reported here was to begin to characterize cytochrome P450-mediated metabolism of dantrolene in the horse and describe the pharmacokinetics of the compound, formulated as a capsule or a compounded paste formulation, following oral administration. Dantrolene is rapidly metabolized to 5-hydroxydantrolene both in vivo and in vitro. Preliminary work with equine liver microsomes suggest that two enzymes are responsible for the metabolism of dantrolene, as evidenced by two distinct K m values, one at high and one at low substrate concentrations. For the pharmacokinetic portion of the study, a randomized, balanced 2-way crossover design was employed wherein eight healthy horses received a single oral dose of either capsules or paste followed by a 4week washout period prior to administration of the second formulation to the same horse. Blood samples were collected at time 0 (prior to drug administration) and at various times up to 96h postdrug administration. Plasma samples were analyzed using liquid chromatography-mass spectrometry and data analyzed using both noncompartmental and compartmental analysis. Peak plasma concentrations were 28.9±21.6 and 37.8±12.8ng/mL for capsules and paste, respectively and occurred at 3.8h for both formulations. Dantrolene and its major metabolite were both below the limit of detection in both plasma and urine by 168h postadministration.

Original languageEnglish (US)
Pages (from-to)238-246
Number of pages9
JournalJournal of Veterinary Pharmacology and Therapeutics
Volume34
Issue number3
DOIs
StatePublished - Jun 2011

Fingerprint

Dantrolene
pharmacokinetics
Horses
Pharmacokinetics
horses
Ointments
metabolism
Capsules
Neuromuscular Agents
rhabdomyolysis
muscle relaxants
Rhabdomyolysis
liver microsomes
Liver Microsomes
cytochrome P-450
Liquid Chromatography
Cross-Over Studies
Cytochrome P-450 Enzyme System
oral administration
liquid chromatography

ASJC Scopus subject areas

  • Pharmacology
  • veterinary(all)

Cite this

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abstract = "Dantrolene is a skeletal muscle relaxant used commonly in performance horses to prevent exertional rhabdomyolysis. The goal of the study reported here was to begin to characterize cytochrome P450-mediated metabolism of dantrolene in the horse and describe the pharmacokinetics of the compound, formulated as a capsule or a compounded paste formulation, following oral administration. Dantrolene is rapidly metabolized to 5-hydroxydantrolene both in vivo and in vitro. Preliminary work with equine liver microsomes suggest that two enzymes are responsible for the metabolism of dantrolene, as evidenced by two distinct K m values, one at high and one at low substrate concentrations. For the pharmacokinetic portion of the study, a randomized, balanced 2-way crossover design was employed wherein eight healthy horses received a single oral dose of either capsules or paste followed by a 4week washout period prior to administration of the second formulation to the same horse. Blood samples were collected at time 0 (prior to drug administration) and at various times up to 96h postdrug administration. Plasma samples were analyzed using liquid chromatography-mass spectrometry and data analyzed using both noncompartmental and compartmental analysis. Peak plasma concentrations were 28.9±21.6 and 37.8±12.8ng/mL for capsules and paste, respectively and occurred at 3.8h for both formulations. Dantrolene and its major metabolite were both below the limit of detection in both plasma and urine by 168h postadministration.",
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