Pharmacokinetic and pharmacodynamic interaction for a binary mixture of chlorpyrifos and diazinon in the rat.
Pharmacokinetic and pharmacodynamic interaction for a binary mixture of chlorpyrifos and diazinon in the rat.
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DOI：
10.1016/j.taap.2004.09.004
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发表时间：
2005-05
影响因子：
3.8
通讯作者：
C. Timchalk;T. Poet;Melissa N. Hinman;Andrea L. Busby;A. Kousba
中科院分区：
文献类型：
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作者：
C. Timchalk;T. Poet;Melissa N. Hinman;Andrea L. Busby;A. Kousba
毒死蜱(CPF)和二氮磷(DZN)是两种常用的有机磷(OP)杀虫剂，存在同时暴露的可能性。有机磷农药暴露的主要神经毒性效应是乙酰胆碱酯酶(AChE)的抑制。本研究评价了CPF和DZN对大鼠急性二元染毒的药代动力学和药效学影响。大鼠灌胃给予CPF、DZN或CPF/DZN混合物(0、15、30、60 mg/kg)和全血(血浆和RBC)，分别于给药后0、3、6、12、24 h取脑，24 h取尿，分别测定毒死蜱、DZN及其代谢产物3，5，6-三氯-2-吡啶醇(TCP)和2-异丙基-4-甲基-6-羟基嘧啶(IMHP)的含量，并检测脑、RBC和血浆中胆碱酯酶(ChE)的抑制作用。CPF/DZN低剂量(15/15 mg/kg)联合染毒不改变CPF、DZN及其代谢物在血液中的药代动力学。高二元剂量(60/60 mg/kg)增加了Cmax和AUC，降低了两种母体化合物的清除量，这可能是由于CPF和DZN对CYP450代谢的竞争所致。在较低剂量，最有可能在职业或环境暴露中遇到的情况下，药物动力学是线性的。无论是单一暴露还是联合暴露，组织中CHE的抑制均呈剂量依赖关系，抑制程度以血浆和红细胞≥脑为主。胆碱酯酶抑制的总体相对效力为CPF/DZN>；CPF>；DZN。在低二元剂量(15/15 mg/kg)没有明显药代动力学相互作用的情况下，ChE反应的比较表明，总体ChE反应是相加的。这些实验是关于农药混合物潜在药代动力学和药效相互作用的重要数据，并将为评估与职业或环境接触这些杀虫剂有关的潜在累积风险提供必要的洞察力。
Chlorpyrifos (CPF) and diazinon (DZN) are two commonly used organophosphorus (OP) insecticides and a potential exists for concurrent exposures. The primary neurotoxic effects from OP pesticide exposures result from the inhibition of acetylcholinesterase (AChE). The pharmacokinetic and pharmacodynamic impact of acute binary exposures of rats to CPF and DZN was evaluated in this study. Rats were orally administered CPF, DZN, or a CPF/DZN mixture (0, 15, 30, or 60 mg/kg) and blood (plasma and RBC), and brain were collected at 0, 3, 6, 12, and 24 h postdosing, urine was also collected at 24 h. Chlorpyrifos, DZN, and their respective metabolites, 3,5,6-trichloro-2-pyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), were quantified in blood and/or urine and cholinesterase (ChE) inhibition was measured in brain, RBC, and plasma. Coexposure to CPF/DZN at the low dose of 15/15 mg/kg did not alter the pharmacokinetics of CPF, DZN, or their metabolites in blood. A high binary dose of 60/60 mg/kg increased the Cmaxand AUC and decreased the clearance for both parent compounds, likely due to competition between CPF and DZN for CYP450 metabolism. At lower doses, most likely to be encountered in occupational or environmental exposures, the pharmacokinetics were linear. A dose-dependent inhibition of ChE was noted in tissues for both the single and coexposures, and the extent of inhibition was plasma > RBC ≥ brain. The overall relative potency for ChE inhibition was CPF/DZN > CPF > DZN. A comparison of the ChE response at the low binary dose (15/15 mg/kg), where there were no apparent pharmacokinetic interactions, suggested that the overall ChE response was additive. These experiments represent important data concerning the potential pharmacokinetic and pharmacodynamic interactions for pesticide mixtures and will provide needed insight for assessing the potential cumulative risk associated with occupational or environmental exposures to these insecticides.