Pharmacokinetics and metabolism of dantrolene in horses

DiMaio Knych, H.K., Arthur, R.M., Taylor, A., Moeller, B.C., Stanley, S.D. Pharmacokinetics and metabolism of dantrolene in horses. J. vet. Pharmacol. Therap.34, 238–246. 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 Km 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 4 week 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 96 h 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 ± 12.8 ng/mL for capsules and paste, respectively and occurred at 3.8 h for both formulations. Dantrolene and its major metabolite were both below the limit of detection in both plasma and urine by 168 h postadministration.