Metabolism and pharmacokinetics of a single oral dose of O-4-bromo-2,5-dichlorophenyl O-methyl phenylphosphonothioate (Leptophos) in hens.
Metabolism and pharmacokinetics of a single oral dose of O-4-bromo-2,5-dichlorophenyl O-methyl phenylphosphonothioate (Leptophos) in hens.
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母鸡单次口服剂量的 O-4-溴-2,5-二氯苯基 O-甲基苯基硫代膦 (Leptophos) 的代谢和药代动力学。
DOI：
10.1016/0041-008x(80)90229-x
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发表时间：
1980
影响因子：
3.8
通讯作者：
M. Abou‐Donia
中科院分区：
文献类型：
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作者：
M. Abou‐Donia
研究了蛋鸡口服50 mg/kg(0.9μCi/只)[苯基~(14)C]-[苯基]-2，5-二氯苯基-O-甲基[~(14)C]苯基硫代膦后，亚神经毒性剂量的利硫磷的代谢和药代动力学。这项研究为迟发性神经毒性的物种选择性与物种间药代动力学和新陈代谢的差异有关的假设增加了确凿的证据。口服瘦磷在母鸡体内代谢和排泄缓慢。在20天的实验中，大部分放射性(86.5%)被排出。相当大的剂量分别沉积在蛋清和蛋黄中，分别为-3.4%和2.5%。只有1.3%的二氧化碳在呼出的二氧化碳中排出。组织中放射性在给药后12小时达峰值，为剂量的14.6%，20天后降至6.2%(峰值的42.6%)。胆汁中的14C浓度最高，其次是胆、肾、脂肪组织和肝脏。大脑、脊髓和坐骨神经受瘦磷的神经毒性影响，在整个实验过程中有较小但保持不变的浓度。口服[~(14)C]瘦磷后，~(14)C体内负荷随时间的变化呈双指数变化。因此，可以用两室开放系统模型来定义鳞磷的生理配置。放射性排泄缓慢，β值为0.05d−1，半衰期为12.0d。Leptophos是唯一在神经组织、肌肉、脂肪和血液中发现的化合物。排泄物和肝脏中的大部分放射性物质被鉴定为不变的瘦磷，并有少量的极性代谢物。瘦磷的代谢去向可以根据其脂类溶解和组织结合的物理性质以及该化合物主要的胆汁分泌和胃肠道排泄来解释。
The metabolism and pharmacokinetics of a subneurotoxic dose of leptophos were determined in laying hens following a single oral dose of 50 mg/kg (0.9 μCi/hen) of [phenyl14C]leptophos (O-4-bromo-2,5-dichlorophenyl O-methyl [14C]phenylphosphonothioate). This study adds confirmatory evidence to the hypothesis that species selectivity for delayed neurotoxicity is related to interspecies differences in pharmacokinetics and metabolism. Oral leptophos was metabolized and excreted slowly in hens. The major portion of the radioactivity (86.5%) was excreted during the 20-day experiment. Significant amounts of the dose were deposited in egg albumen and yolk—3.4 and 2.5%, respectively. Only 1.3% was excreted in expired CO2. Radioactivity in tissues reached a peak of 14.6% of the dose 12 hr after administration; radioactivity decreased to 6.2% after 20 days (42.6% of peak value). The highest14C concentration was present in the bile, followed by the gall bladder, kidney, adipose tissue, and liver. Brain, spinal cord, and sciatic nerve, which are affected by the neurotoxicity of leptophos, had smaller but constant concentrations throughout the experiment. Following the oral administration of [14C]leptophos the change in the14C body burden with time was biexponential. The physiological disposition of leptophos may therefore be defined in terms of a two-compartment open-system model. Radioactivity was excreted at a slow rate, β value of 0.05 day−1, corresponding to a half-life of 12.0 days. Leptophos was the only compound identified in nerve tissues, muscle, fat, and blood. Most of the radioactive substances in the excreta and liver were identified as unchanged leptophos with minor amounts of polar metabolites. The metabolic fate of leptophos can be explained on the basis of its physical properties of lipid solubility and tissue binding, and the predominant biliary secretion and gastrointestinal excretion of the compound.