Data_Sheet_1_Prednisolone in Dogs—Plasma Exposure and White Blood Cell Response.PDF

Glucocorticoids such as prednisolone are commonly used in dogs but there is sparse quantitative pharmacokinetic and pharmacodynamic information of this drug in this species. The objective of this study was to quantitatively characterize the concentration-effect relationship for prednisolone in dogs on neutrophil and lymphocyte trafficking and cortisol suppression. Nine beagles, 2–12 years old and part of a group for teaching/research were used in a 4-way crossover experiment including two treatments, active or placebo, administered either per os (PO) or intravenously (IV). Plasma was analyzed for prednisolone and cortisol using ultra-high performance liquid chromatography – tandem mass spectrometry. Leucocyte counts were performed in whole blood. Data was then analyzed by non-linear mixed effect modeling to estimate pharmacokinetic and pharmacodynamic parameters. After administration of prednisolone sodium succinate IV, the typical value (between subject variation) for total body prednisolone clearance was 1,370 ml/h·kg (13.4%). The volumes of the central and peripheral compartment were 2,300 ml/kg (10.7%) and 600 ml/kg (16.0%), respectively. The terminal plasma half-life was 1.7 h. The prednisolone plasma concentration producing 50% of the maximum response was 10 ng/mL (90.3%), 22.5 ng/ml (52.3%) and 0.04 ng/mL (197.3%) for neutrophil, lymphocyte and cortisol response, respectively. The administered dose (1 mg/kg) increased neutrophil and decreased lymphocyte numbers but not over the entire dosage interval of 24 h, due to the short half-life. However, glucocorticoids have a wide range of responses. An anti-inflammatory response due to altered gene transcription might have a longer duration. Future studies on the anti-inflammatory potency together with data presented are needed to optimize future dosage recommendations in dogs.

以泼尼松龙（prednisolone）为代表的糖皮质激素在犬临床中应用广泛，但该物种中关于此药物的定量药代动力学与药效动力学相关信息仍较为匮乏。本研究旨在定量表征泼尼松龙在犬体内针对中性粒细胞、淋巴细胞迁移以及皮质醇抑制的浓度-效应关系。本研究纳入9只2~12岁、用于教学/研究的比格犬，开展四向交叉试验，设置口服（per os, PO）与静脉注射（intravenous, IV）两种给药途径，以及活性药物与安慰剂两种处理方案。采用超高效液相色谱-串联质谱法（ultra-high performance liquid chromatography – tandem mass spectrometry）检测血浆中泼尼松龙与皮质醇浓度，并对全血样本进行白细胞计数。随后通过非线性混合效应模型对采集的数据进行分析，以估算药代动力学与药效动力学参数。经琥珀酸泼尼松龙（prednisolone sodium succinate）静脉注射给药后，犬体内泼尼松龙的全身总清除率典型值为1370 mL/h·kg，个体间变异系数为13.4%；中央室与外周室的分布容积分别为2300 mL/kg（10.7%）与600 mL/kg（16.0%），血浆终末半衰期为1.7 h。使中性粒细胞、淋巴细胞与皮质醇响应分别达到最大效应50%时的泼尼松龙血浆浓度依次为10 ng/mL（90.3%）、22.5 ng/mL（52.3%）与0.04 ng/mL（197.3%）。给药剂量为1 mg/kg时，犬体内中性粒细胞数量升高、淋巴细胞数量降低，但该效应并未覆盖完整的24 h给药间隔，这与药物较短的半衰期有关。不过糖皮质激素的生物学效应范围广泛，由基因转录改变介导的抗炎反应可能具有更长的持续时间。未来需结合本研究数据与抗炎药效相关研究结果，以优化犬类的临床给药方案推荐。