Hunyadi L, Papich M G, Pusterla N
William R Pritchard Veterinary Medical Teaching Hospital, UC Davis School of Veterinary Medicine, Davis, CA, USA.
J Vet Pharmacol Ther. 2015 Jun;38(3):243-8. doi: 10.1111/jvp.12176. Epub 2014 Oct 20.
The purpose of this study was to determine the pharmacokinetics of the FDA-approved labeled dose of diclazuril and compare it to a low dose in plasma and CSF in adult horses. During each research period, six healthy adult horses received 0.5 mg/kg of 1.56% diclazuril pellets (Protazil(TM) , Merck Animal Health) compared to the approved labeled dose of 1 mg/kg orally once in two separate phases. A dose of 0.5 mg/kg was calculated to each horse's weight. Blood was then collected immediately before diclazuril administration and then at regular intervals up to a 168 h. After the last blood collection following the single dose at hour 168, a once daily oral dose was administered for the next 10 days to ensure the drug's concentration reached steady-state. To determine the CSF concentration at steady-state, CSF samples were collected after the 9th oral dose. Blood was then collected after the 10th dose and then at regular intervals up to 168 h. A washout period of 4 weeks was allowed before repeating this protocol for the FDA-labeled dose at 1 mg/kg. Plasma and CSF samples were analyzed by high-pressure liquid chromatography. A one-compartment pharmacokinetic model with first-order oral absorption was fitted to the single administration data. Steady-state pharmacokinetics was performed using noncompartmental analysis for steady-state analysis. The mean (standard deviation) concentration of diclazuril in CSF following the low dose was 26 ng/mL (5 ng/mL), while CSF in the FDA-labeled dose was 25 ng/mL (4 ng/mL), P = 0.3750. Substantial accumulation in plasma occurred at steady-state after the 10th dose for both doses. The results of this study show that diclazuril pellets given at the approved label dose and a lower dose both produce similar plasma drug concentrations at steady-state and attain plasma and CSF concentrations known to inhibit Sarcocystis neurona in cell culture.
本研究的目的是确定美国食品药品监督管理局（FDA）批准的地克珠利标记剂量的药代动力学，并将其与成年马血浆和脑脊液中的低剂量进行比较。在每个研究阶段，六匹健康成年马接受0.5mg/kg的1.56%地克珠利颗粒剂（Protazil™，默克动物保健），而批准的标记剂量为1mg/kg，分两个不同阶段口服一次。根据每匹马的体重计算出0.5mg/kg的剂量。然后在给予地克珠利之前立即采集血液，之后每隔一定时间采集一次，直至168小时。在第168小时单剂量给药后的最后一次采血后，接下来10天每天口服一次剂量，以确保药物浓度达到稳态。为了确定稳态时的脑脊液浓度，在第9次口服给药后采集脑脊液样本。然后在第10次给药后采集血液，之后每隔一定时间采集一次，直至168小时。在重复1mg/kg的FDA标记剂量的方案之前，允许有4周的洗脱期。血浆和脑脊液样本通过高压液相色谱法进行分析。将具有一级口服吸收的单室药代动力学模型拟合到单次给药数据。使用非房室分析法进行稳态药代动力学分析以进行稳态分析。低剂量后脑脊液中地克珠利的平均（标准差）浓度为26ng/mL（5ng/mL），而FDA标记剂量的脑脊液中为25ng/mL（4ng/mL），P = 0.3750。两种剂量在第10次给药后稳态时血浆中均出现大量蓄积。本研究结果表明，以批准的标记剂量和较低剂量给予地克珠利颗粒剂，在稳态时产生的血浆药物浓度相似，并且达到了已知在细胞培养中抑制神经肉孢子虫的血浆和脑脊液浓度。
