PHARMACOKINETICS OF INTRAVENOUSLY ADMINISTERED DANTROLENE AND ITS 5-HYDROXY METABOLITE IN DOGS

Dantrolene, a direct acting muscle relaxant used orally for spasticity, has appeared to be effective in the prevention and treatment of malignant hyperthermia in man and animals when administered intravenously. Its pharmacokinetics following intravenous administration have been studied in dogs. Concentrations of dantrolene and its metabolites in plasma, urine, and bile were determined by high-performance liquid chromatography. Recovery of unchanged drug and reduced metabolites was negligible; of the hydroxy metabolite 2% was found in the urine and about 25% in the bile. The half-life of 5-hydroxydantrolene was shorter than that of the parent drug as demonstrated by administration of the metabolite. The apparent renal clearance of 5-hydroxydantrolene was independent of creatinine clearance, urine flow and pH, and appeared to be reduced in the presence of probenecid. Bile to plasma ratios of the hydroxy metabolite were high with biliary concentrations far exceeding the maximum solubility in water. The results of this pilot study indicate that hydroxylation is primarily responsible for the excretion of the dantrolene molecule from the body.