Kate Burbery , Robert J. Brosnan , Alessia Cenani , Marcela Machado , Heather K. Knych
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Concentrations over time for each compound were fit to noncompartmental models using commercial software. Calculated pharmacokinetic parameters were compared using either repeated-measures <span>anova</span> if normally distributed or Wilcoxon signed-rank tests if not. Differences between agents were significant when <em>p</em> < 0.05 after adjustments for multiple comparisons.</div></div><div><h3>Results</h3><div>Remimazolam was undetectable in the plasma of all sheep by 3 hours, whereas midazolam and diazepam concentrations were still quantifiable 10 hours after injection. Median (range) clearance rate from plasma was 103 (61–256), 22 (9.6–37) and 38 (20–46) mL kg<sup>–1</sup> minute<sup>–1</sup> 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.</div></div><div><h3>Conclusions and clinical relevance</h3><div>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.</div></div>","PeriodicalId":23626,"journal":{"name":"Veterinary anaesthesia and analgesia","volume":"52 2","pages":"Pages 183-191"},"PeriodicalIF":1.9000,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetics of remimazolam, midazolam and diazepam in sheep\",\"authors\":\"Kate Burbery , Robert J. Brosnan , Alessia Cenani , Marcela Machado , Heather K. 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引用次数: 0
摘要
目的:建立三种苯二氮卓类药物及其代谢物在绵羊体内的药动学模型。研究设计:一项非盲法、前瞻性、实验性研究。动物:6只成年汉普郡-萨福克杂交绵羊(3只母羊,3只阉割公羊),体重73±3公斤(平均±标准差)。方法:每只羊分别静脉给药雷马唑仑、咪达唑仑和地西泮,并在10小时内的18个时间点采血。采用HPLC-MS/MS同时测定母体苯二氮卓类药物(代谢物)对雷马唑仑(CNS 7054)、咪达唑仑(α-羟咪达唑仑)和地西泮(去甲地西泮、替马西泮、恶西泮)的血浆浓度。使用商业软件将每种化合物的浓度随时间的变化拟合为非区室模型。计算出的药代动力学参数如果是正态分布,则采用重复测量方差分析,如果不是正态分布,则采用Wilcoxon符号秩检验。经多重比较校正后,p < 0.05为差异有统计学意义。结果:3小时后,所有羊的血浆中均检测不到雷马唑仑,而注射10小时后咪达唑仑和地西泮的浓度仍可定量。雷马唑仑、咪达唑仑和地西泮的中位(范围)血浆清除率分别为103(61-256)、22(9.6-37)和38 (20-46)mL kg-1 min -1。雷马唑仑、咪达唑仑和地西泮的中位(范围)终末消除时间分别为9.8(4.6-15)、113(90-271)和246(170-624)分钟。除替马西泮外,代谢物的最终消除时间通常比母体药物长。结论及临床意义:雷马唑仑的消除明显快于咪达唑仑或地西泮。雷马唑仑的快速药代动力学可能对促进镇静后的快速恢复和减少食用动物的药物残留暴露特别有用。
Pharmacokinetics of remimazolam, midazolam and diazepam in sheep
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
Remimazolam was undetectable in the plasma of all sheep by 3 hours, whereas midazolam and diazepam concentrations were still quantifiable 10 hours after injection. Median (range) clearance rate from plasma was 103 (61–256), 22 (9.6–37) and 38 (20–46) mL kg–1 minute–1 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.
期刊介绍:
Veterinary Anaesthesia and Analgesia is the official journal of the Association of Veterinary Anaesthetists, the American College of Veterinary Anesthesia and Analgesia and the European College of Veterinary Anaesthesia and Analgesia. Its purpose is the publication of original, peer reviewed articles covering all branches of anaesthesia and the relief of pain in animals. Articles concerned with the following subjects related to anaesthesia and analgesia are also welcome:
the basic sciences;
pathophysiology of disease as it relates to anaesthetic management
equipment
intensive care
chemical restraint of animals including laboratory animals, wildlife and exotic animals
welfare issues associated with pain and distress
education in veterinary anaesthesia and analgesia.
Review articles, special articles, and historical notes will also be published, along with editorials, case reports in the form of letters to the editor, and book reviews. There is also an active correspondence section.