Dantrolene sodium is a ryanodine receptor 1 antagonist. It is believed to work by inhibiting abnormal calcium release from the sarcoplasmic reticulum, leading to muscle relaxation.1 The pharmacokinetic properties of RYANODEX® (dantrolene sodium) for injectable suspension were investigated in a phase 1 study in healthy volunteers (see table below). RYANODEX® was administered as a continuous (bolus) intravenous push, via a peripheral (forearm) catheter, at a dose of 2.5 mg/kg, and dantrolene and 5-hydroxydantrolene concentrations were measured in serially collected plasma samples. Median Tmax (for dantrolene) was the first time point collected (ie, 1 minute post-dose).
|RYANODEX® dosea||Cmax µg/mL||AUC0-inf µg*h/mL||Half-life (t1/2) hrs||Clearance (CL) L/hr||Volume of distribution (Vd) L|
|2.5 mg/kg||9.0 ± 4.6||77.7 ± 23.2||10.8b ± 2.2||2.5 ± 1.0||36.4 ± 11.7|
a n=15; single dose, healthy conscious volunteers. b Median. There was a dose-proportional increase in plasma exposure of dantrolene and its metabolite, 5-hydroxydantrolene.1 Time to peak dantrolene concentration was observed at the first time point collected. The mean half-life (t1/2) for dantrolene was independent of the RYANODEX dose administered and ranged from 8.5 hours to 11.4 hours over the 1 to 2.5 mg/kg dose range. When prophylactic intravenous dantrolene infusion was administered, whole blood dantrolene concentrations remained at a near steady state level for 3 or more hours after the infusion was completed. Based on assays of whole blood and plasma, slightly greater amounts of dantrolene are associated with red blood cells than with the plasma fraction of blood. Significant amounts of dantrolene are bound to plasma proteins, mostly albumin, and this binding is readily reversible. Binding to plasma protein is not significantly altered by diazepam, diphenylhydantoin, or phenylbutazone. Binding to plasma proteins is reduced by warfarin and clofibrate and increased by tolbutamide. Information concerning the passage of dantrolene across the blood-brain barrier is not available. Dantrolene is found in measurable amounts in blood and urine. Its major metabolites in body fluids are 5-hydroxy dantrolene and an acetylamino metabolite of dantrolene. Another metabolite with an unknown structure appears related to the latter. Dantrolene may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid. Following RYANODEX 2.5 mg/kg dose administration in healthy volunteers, mean peak plasma concentration for the primary metabolite, 5-hydroxydantrolene, was 640 ng/mL, and was achieved by approximately 24 hours post-dose, with an average metabolite-to-parent exposure ratio of 0.27 (AUC0-inf = 21.2 µg*h/mL). Median t1/2 for 5-hydroxydantrolene was 10 hours, the clearance was estimated to be 8.9 L/hr and the terminal phase volume of distribution was 144 L. Dantrolene is metabolized by the liver, and it is possible that its metabolism may be enhanced by drugs known to induce hepatic microsomal enzymes. However, neither phenobarbital nor diazepam appears to affect dantrolene metabolism.