Estimation of the upper limit of human butyrylcholinesterase dose required for protection against organophosphates toxicity: A mathematically based toxicokinetic model
Estimation of the upper limit of human butyrylcholinesterase dose required for protection against organophosphates toxicity: A mathematically based toxicokinetic model
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DOI：
10.1093/toxsci/kfh012
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发表时间：
2004-02-01
影响因子：
3.8
通讯作者：
Pistinner, S
中科院分区：
文献类型：
--
作者：
Ashani, Y;Pistinner, S
人丁酰胆碱酯酶（HuBChE）是一种保护有机磷（OP）中毒的候选药物。一个基于数学的模型进行了验证，并用于更好地了解内源性HuBChE在OP解毒中的作用，并估计增强保护人类免受致命暴露于OP所需的外源性HuBChE剂量。该模型解决了维持人乙酰胆碱酯酶（HuAChE）的一定残留活性所需的HuBChE剂量与以下参数之间的关系：（1）暴露水平和持续时间，（2）OP抑制HuAChE（kA）和HuBChE（kB）的双分子速率常数，以及（3）从酶负荷开始经过的时间。用于计算HuBChE剂量的公式需要了解人血液中的kA/kB和HuBChE消除的速率常数。HuBChE剂量的预测通过体外实验和已发表的人体研究数据进行了验证。这些预测强调了可能降低计算剂量的两个参数：（1）人血浆中毒性较低的OP异构体的快速消耗，以及（2）HuBChE的分布容积明显大于血浆容积。拟议模型的分析的第一部分是集中在急性丸暴露，并表明，上限剂量为134，115，和249毫克/70公斤足以保护红细胞乙酰胆碱酯酶高于30%的基线活动后，挑战与1 LD 50 VX，梭曼，沙林，分别。经验证模型的原理应适用于HuBChE剂量的高级预测，以防止持续暴露于OP。
Human butyrylcholinesterase (HuBChE) is a drug candidate for protection against organophosphates (OP) intoxication. A mathematically based model was validated and employed to better understand the role of the endogenous HuBChE in detoxification of OPs and to estimate the dose of exogenous HuBChE required for enhancing protection of humans from lethal exposure to OPs. The model addresses the relationship between the HuBChE dose needed to maintain a certain residual activity of human acetylcholinesterase (HuAChE) and the following parameters: (1) level and duration of exposure, (2) bimolecular rate constants of inhibition of HuAChE (kA) and HuBChE (kB) by OPs, and (3) time elapsed from enzyme load. The equation derived for the calculation of HuBChE dose requires the knowledge of kA/kB in human blood and the rate constant of HuBChE elimination. Predictions of HuBChE doses were validated by in vitro experiments and data of published human studies. These predictions highlight two parameters that are likely to decrease the calculated dose: (1) the rapid consumption of the less toxic isomers of OPs in human plasma, and (2) the volume of distribution of HuBChE that appears significantly greater than the volume of plasma. The first part of the analysis of the proposed model was focused on acute bolus exposures and suggests that upper limit doses of 134, 115, and 249 mg/70 kg are sufficient to protect RBC AChE above 30% of baseline activity following a challenge with 1 LD50 VX, soman, and sarin, respectively. The principles of the validated model should be applicable for advanced predictions of HuBChE dose for protection against continuous exposures to OPs.