Portugal Felipe Ramon, Lacroix Marlène Z, Roques Béatrice B, Gayrard Véronique, Toutain Pierre-Louis, Bousquet-Mélou Alain
INTHERES, Université de Toulouse, INRAE, ENVT, Toulouse, France.
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France.
J Vet Pharmacol Ther. 2023 Mar;46(2):112-118. doi: 10.1111/jvp.13111. Epub 2023 Jan 24.
Doxycycline is an antibiotic widely used in pig farming. As with all antibiotics, only the free concentrations are considered to be bacteriologically active. Historically, the free fraction (fu) in pig plasma has been estimated at 7%, which, given the effective dosage regime used in pigs, leads to free plasma concentrations of doxycycline largely lower than the minimum inhibitory concentrations of the target pathogens. This apparent inconsistency led us to reassess plasma protein binding of doxycycline in pigs. Using an equilibrium dialysis method, the extent of doxycycline binding was measured individually in 26 pigs for total doxycycline concentration ranging from 10 to 1000 μmol/L. Analysis of the data using a non-linear mixed-effects model demonstrated linearity of plasma protein binding with a mean fu value of 31% and a relatively low inter-subject variability of approximately 10%. This new data showing that the free fraction is four times greater than what could have been anticipated from historical data is discussed in particular for the calculation of the PK/PD cut-offs, which are used to establish the clinical breakpoints for antimicrobial susceptibility testing.
多西环素是一种在养猪业中广泛使用的抗生素。与所有抗生素一样，只有游离浓度才被认为具有细菌学活性。从历史上看，猪血浆中的游离分数（fu）估计为7%，鉴于猪所使用的有效剂量方案，这导致多西环素的游离血浆浓度大大低于目标病原体的最低抑菌浓度。这种明显的不一致促使我们重新评估猪体内多西环素的血浆蛋白结合情况。采用平衡透析法，在26头猪中分别测定了多西环素总浓度在10至1000μmol/L范围内的结合程度。使用非线性混合效应模型对数据进行分析，结果表明血浆蛋白结合呈线性，平均fu值为31%，个体间变异性相对较低，约为10%。特别是在计算PK/PD临界值时，讨论了这一新数据，该临界值用于确定抗菌药物敏感性试验的临床断点，此新数据表明游离分数比根据历史数据预期的大四倍。
