Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Hatay Mustafa Kemal, Antakya, Hatay, Türkiye.
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Selcuk, Konya, Türkiye.
Vet Med Sci. 2024 Nov;10(6):e70047. doi: 10.1002/vms3.70047.
This study aimed to investigate the plasma and milk pharmacokinetics, as well as the withdrawal time (WT) from milk of tolfenamic acid (2 and 4 mg/kg) following intravenous (IV) administration to eight healthy lactating Akkaraman sheep.
The trial was conducted in two periods in accordance with a crossover pharmacokinetic design. The concentrations of tolfenamic acid in the plasma and milk were determined using high-pressure liquid chromatography and evaluated using non-compartmental analysis. The WT of tolfenamic acid in milk was calculated using the WT 1.4 software.
Compared to the 2 mg/kg dose, plasma volume of distribution at steady state (from 0.43 to 0.50 L/kg), terminal elimination half-life (from 2.41 to 4.14 h) and dose-normalized area under the plasma concentration-time curve (AUC, from 9.46 to 30.11 h µg/mL) increased, whereas total body clearance (from 0.21 to 0.13 L/h/kg) decreased at the 4 mg/kg dose. The peak milk concentration (C) and AUC values in milk were 0.26 µg/mL and 0.28 h µg/mL, respectively, for 2 mg/kg, and 0.43 µg/mL and 0.55 h µg/mL, respectively, for 4 mg/kg. Although the dose-normalized C of milk decreased depending on the dose, no difference was observed in dose-normalized AUC. The AUC/AUC ratio was 0.03 for 2 mg/kg and 0.02 for 4 mg/kg. The WT values calculated for milk at dosages of 2 and 4 mg/kg were 3 and 4 h, respectively.
A decrease in plasma elimination and an increase in plasma concentration of tolfenamic acid were observed depending on the dose. Tolfenamic acid lowly passed into sheep's milk at 2 and 4 mg/kg doses. This study may provide valuable information for clinicians' decision-making processes.
本研究旨在探讨托芬那酸（2 和 4mg/kg）静脉给药后在健康泌乳阿卡尔曼羊体内的血浆和乳汁药代动力学特征，以及乳汁中的消除半衰期（withdrawal time，WT）。
本试验采用交叉药代动力学设计，分两期进行。采用高效液相色谱法测定血浆和乳汁中托芬那酸的浓度，并采用非房室模型分析法进行评价。采用 WT 1.4 软件计算托芬那酸在乳汁中的 WT。
与 2mg/kg 剂量相比，4mg/kg 剂量时，稳态分布容积（从 0.43 升至 0.50L/kg）、末端消除半衰期（从 2.41 升至 4.14h）和剂量标准化的血浆浓度-时间曲线下面积（area under the plasma concentration-time curve，AUC，从 9.46 升至 30.11h·µg/mL）增加，而总清除率（从 0.21 降至 0.13L/h/kg）降低。2mg/kg 剂量时，乳汁中 C 和 AUC 分别为 0.26µg/mL 和 0.28h·µg/mL，4mg/kg 剂量时，C 和 AUC 分别为 0.43µg/mL 和 0.55h·µg/mL。尽管随着剂量的增加，乳汁中剂量标准化的 C 降低，但 AUC 无差异。AUC/AUC 比值分别为 2mg/kg 时的 0.03 和 4mg/kg 时的 0.02。2mg/kg 和 4mg/kg 剂量时乳汁的 WT 值分别为 3h 和 4h。
托芬那酸的血浆消除减少，血浆浓度增加，这与剂量有关。2mg/kg 和 4mg/kg 剂量时，托芬那酸少量进入绵羊乳汁。本研究可为临床医生的决策过程提供有价值的信息。
