Objective

To describe the pharmacokinetics of buprenorphine in dogs following administration of a high-concentration formulation of buprenorphine.

Study design

Prospective, randomized, crossover study.

Animals

A total of six healthy male intact Beagle dogs, aged 9–13 months and weighing 10.3 ± 1.4 kg (mean ± standard deviation).

Methods

Dogs were randomized to be administered buprenorphine (0.12 mg kg^–1; Simbadol, 1.8 mg mL^–1) via the intravenous (lateral saphenous) or subcutaneous (dorsal interscapular) route followed by the alternative route of administration after a 14 day interval. Blood was sampled before administration and at set times up to 72 hours after injection. Plasma buprenorphine concentration was measured using liquid chromatography–tandem mass spectrometry.

Results

A three-compartment model with zero or biphasic rapid and slow first-order input in (intravenous or subcutaneous data, respectively) and first-order elimination from the central compartment best fitted the data. The rapid first-order input accounted for 63% of the dosage absorption. Typical values (% interindividual variability) for the three compartment volumes were 900 (33), 2425 (not estimated) and 6360 (28) mL kg^–1. The metabolic and two distribution clearances were 25.7 (21), 107.5 (74) and 5.7 (61) mL minute^–1 kg^–1. The absorption half-life for the fast absorption phase was 8.9 minutes with a 0.7 (103) minute delay. The absorption half-life for the slow absorption phase was 347 minutes with a 226 (42) minute delay. Median (range) bioavailability calculated from noncompartmental analysis was 143 (80–239)%. Calculated terminal half-life was 963 minutes.

Conclusions and clinical relevance

The high-concentration formulation of buprenorphine administered subcutaneously had a large volume of distribution and a rapid absorption phase followed by slower, delayed absorption. The high estimate of bioavailability should be interpreted with caution as values above 100% are most commonly related to experimental issues.

中文翻译：

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高浓度丁丙诺啡（辛巴多）制剂在雄性犬体内的药代动力学

客观的

描述给予高浓度丁丙诺啡制剂后丁丙诺啡在狗体内的药代动力学。

学习规划

前瞻性、随机、交叉研究。

动物

共有 6 只健康的雄性完整比格犬，年龄 9-13 个月，体重 10.3 ± 1.4 kg（平均值 ± 标准差）。

方法

狗被随机分配接受丁丙诺啡（0.12 mg kg ^–1；辛巴多，1.8 mg mL ^–1），通过静脉内（外侧隐静脉）或皮下（背侧肩胛间）途径给药，间隔 14 天后采用替代给药途径。在给药前和注射后长达 72 小时的设定时间采集血液样本。使用液相色谱-串联质谱法测量血浆丁丙诺啡浓度。

结果

具有零或双相快速和慢速一阶输入（分别为静脉内或皮下数据）和中央隔室的一阶消除的三室模型最适合数据。快速一级输入占剂量吸收的63%。三个隔室容积的典型值（个体差异百分比）分别为 900 (33)、2425（未估计）和 6360 (28) mL kg ^–1。代谢清除率和两次分布清除率分别为 25.7 (21)、107.5 (74) 和 5.7 (61) mL min ^–1 kg ^–1. 快速吸收阶段的吸收半衰期为 8.9 分钟，延迟为 0.7 (103) 分钟。缓慢吸收阶段的吸收半衰期为 347 分钟，延迟 226 (42) 分钟。从非房室分析计算的中位（范围）生物利用度为 143 (80–239)%。计算的终末半衰期为 963 分钟。

结论和临床相关性

皮下给药的高浓度丁丙诺啡制剂具有大的分布容积和快速吸收阶段，随后吸收较慢、延迟吸收。生物利用度的高估计值应谨慎解释，因为高于 100% 的值通常与实验问题有关。