Year: 2024
Type: article
Abstract: OBJECTIVE: To model pharmacokinetics of three benzodiazepines and their metabolites in sheep. STUDY DESIGN: A nonblinded, prospective, experimental study. ANIMALS: A group of six adult Hampshire-Suffolk cross-bred sheep (three females, three castrated males), 73 ± 3 kg (mean ± standard deviation). METHODS: Remimazolam, midazolam and diazepam were coadministered as an intravenous (IV) bolus to each sheep, and blood was sampled at 18 time points over 10 hours. HPLC-MS/MS was used to simultaneously measure plasma concentrations of the parent benzodiazepines (metabolites) for remimazolam (CNS 7054), midazolam (α-hydroxymidazolam) and diazepam (nordiazepam, temazepam, oxazepam). Concentrations over time for each compound were fit to noncompartmental models using commercial software. Calculated pharmacokinetic parameters were compared using either repeated-measures anova if normally distributed or Wilcoxon signed-rank tests if not. Differences between agents were significant when p < 0.05 after adjustments for multiple comparisons. RESULTS: for remimazolam, midazolam and diazepam, respectively. Median (range) terminal elimination half-time was 9.8 (4.6-15), 113 (90-271) and 246 (170-624) minutes for remimazolam, midazolam and diazepam, respectively. Except for temazepam, terminal elimination half-times were generally longer for metabolites than for their parent drug. CONCLUSIONS AND CLINICAL RELEVANCE: Remimazolam elimination is significantly faster than either midazolam or diazepam. The rapid pharmacokinetics of remimazolam may be particularly useful to facilitate fast recovery from sedation and minimize drug residue exposures in food-producing animals.
Language: English
Subfield: Small Animals
Field: Veterinary
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,000
OpenAlex ID: W4405877113