Pharmacokinetics of oxytetracycline in the white shrimp, Litopenaeus setiferus
Pharmacokinetics of oxytetracycline in the white shrimp, Litopenaeus setiferus
复制标题
土霉素在白对虾体内的药代动力学
DOI：
10.1016/s0044-8486(03)00451-4
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发表时间：
2004
期刊：
影响因子：
4.5
通讯作者：
J. Shah
中科院分区：
文献类型：
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作者：
L. Reed;T. Siewicki;J. Shah
虾是美国最有价值的海鲜之一，其中很大一部分是养殖的。至少有7种弧菌和其他病原体经常在养殖的某个阶段感染对虾，对生产力产生深远的影响。这里描述的研究是为了优化剂量，以便在最大限度地减少环境残留的同时，实现有效的疾病控制。对广谱抗生素土霉素(OTC)在对虾体内的药代动力学进行了研究，以确定其在对虾体内的分布特征，并确定其在养殖对虾中用于治疗弧菌感染的潜力。血管内给药和采样技术被开发出来，因为这是第一次使用存活采样进行对虾的药代动力学研究。单次低、高剂量血管内注射和采集血淋巴后，评价OTC的药代动力学。全身给药后观察组织分布，并用超滤技术研究对虾血淋巴中蛋白质的结合情况。用高效液相色谱法测定了OTC的血淋巴和组织水平，并符合合适的药代动力学模型，以表征OTC在虾体内的分布。血淋巴中OTC的浓度-时间曲线可用双指数方程很好地描述，表明OTC在对虾体内的药代动力学为二室。分布半衰期为2.05±0.48 h，消除半衰期为22.27±7.45 h。全身清除和稳态分布容量分别为78.04±24.33ml/h/kg和2304±280ml/kg。尾部肌肉中的OTC水平(占总体重的百分比)显著低于血淋巴中的OTC水平，从而最大限度地减少了OTC处理后可食用虾组织中OTC残留的问题。OTC的血淋巴蛋白结合率很低，系统中几乎80%的游离OTC可用，支持观察到的大量分布。尽管虾的解剖结构简单，体积小，寿命短，但血管内给药后，OTC在虾体内的分布表现出广泛的药代动力学特征，如消除半衰期长，分布体积大，尾部肌肉组织中OTC残留的可能性低。我们的结果表明，给予治疗剂量的OTC(即足以超过MIC)的虾在停药14天后在可食用组织中不会检测到OTC水平。然而，饲料中OTC的盐形式和配方会影响溶出度、生物利用度、药代动力学，从而影响组织残留。因此，停药时间不应该是特定于药物或制剂的，而是特定于产品和制剂的。这些结果必须通过我们实验室正在进行的口服剂量研究和生物利用度测定来证实。
Shrimp are among the most highly valued seafood in the US, and a large proportion are cultured. At least seven species of Vibrio bacteria and other pathogens often infect shrimp during some stage of culture, having profound impacts on productivity. The research described herein was conducted to optimize dosing to allow effective disease control while minimizing environmental residues. Pharmacokinetics of oxytetracycline (OTC), a broad spectrum antibiotic were evaluated in the white shrimp, Litopenaeus setiferus, to characterize its disposition and to determine its potential for use in farm-raised shrimp for the treatment of Vibrio infections. Intravascular dosing and sampling techniques were developed, since this was the first pharmacokinetic study in shrimp using survival sampling. Pharmacokinetics of OTC were evaluated after single low and high bolus intravascular doses and hemolymph sampling. Tissue distribution was investigated after systemic administration, and protein binding was studied in hemolymph isolated from shrimp using ultrafiltration. The hemolymph and tissue levels of OTC were measured by HPLC and fitted to appropriate pharmacokinetic models to characterize the disposition of OTC in shrimp. Hemolymph OTC concentration–time profiles were well described by a biexponential equation indicative of two-compartment pharmacokinetics of OTC in shrimp. The half-lives of distribution and elimination were 2.05±0.48 and 22.27±7.45 h, respectively. Systemic clearance and steady-state volume of distribution were 78.04±24.33 ml/h/kg and 2304±280 ml/kg, respectively. OTC levels in tail muscle (% of total body burden) were significantly lower than in hemolymph, minimizing concerns of OTC residue in edible shrimp tissue after OTC treatment. Hemolymph protein binding of OTC was found to be low with almost 80% free OTC available systemically, supporting the high volume of distribution observed. Despite the simple anatomy, small size and short life span of shrimp, the disposition of OTC in shrimp after intravascular dosing showed pharmacokinetic characteristics indicative of extensive tissue distribution, such as a long elimination half-life and a high volume of distribution, with the low potential for OTC residues in tail muscle tissue. Our results suggest that shrimp given a therapeutic dose of OTC (i.e., sufficient to exceed the MIC) will have no detectable OTC levels in edible tissues 14 days following withdrawal. However, the salt form and formulation of OTC in feeds can impact dissolution, bioavailability, pharmacokinetics and, hence, tissue residues. Thus, withdrawal times should not be drug or agent specific but product and formulation specific. These results must be confirmed with oral dosing studies and bioavailability determinations that are underway in our laboratory.