Pharmacokinetics and Pharmacodynamics of chlorpyrifos and 3,5,6-trichloro-2-pyridinol in rat saliva after chlorpyrifos administration.
Pharmacokinetics and Pharmacodynamics of chlorpyrifos and 3,5,6-trichloro-2-pyridinol in rat saliva after chlorpyrifos administration.
复制标题
毒死蜱给药后大鼠唾液中毒死蜱和 3,5,6-三氯-2-吡啶醇的药代动力学和药效学。
DOI：
10.1093/toxsci/kfs251
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Timchalk,Charles
中科院分区：
文献类型：
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作者：
Smith,JordanNed;Wang,Jun;Lin,Yuehe;Klohe,EliseM;Timchalk,Charles
人们已经开发出用于对有机磷农药氯吡虫啉（CPF）进行无创生物监测的传感器，先前的研究表明，CPF的代谢物3,5,6-三氯-2-吡啶醇（TCPy）在暴露于TCPy后会一致地进入唾液中。本研究的目的是定量评价CPF和TCPy在唾液中的体内药代动力学和药效学。将CPF （0.5 ~ 5mg/kg）与匹罗卡品（~13mg/kg）联合给药，采集唾液和血液，定量测定CPF、TCPy和胆碱酯酶（ChE）活性。实验结果表明，CPF在静脉给药后代谢迅速。低剂量CPF （0.5mg/kg）形成TCPy的速度比高剂量CPF慢，可能是由于血浆蛋白与CPF结合的差异。唾液中CPF仅在采样的第一个时间点（0-15min）测量，表明分配低，代谢快。形成后，TCPy在血液和唾液中的药代动力学非常相似。唾液/血液TCPy浓度比不受血液中TCPy浓度、唾液流速或唾液pH值的影响，与先前的研究一致。血浆中ChE活性呈剂量依赖性降低，唾液中ChE活性变化很大，与剂量无关。修正了CPF基于生理学的药代动力学和药效学模型，并对数据进行了较好的预测。人们设想，将唾液中的TCPy等生物监测化合物与计算建模相结合，将形成一种测量农药暴露于易感人群（如农业工人）的方法。
Sensors have been developed for noninvasive biomonitoring of the organophosphate pesticide chlorpyrifos (CPF), and previous studies have suggested consistent partitioning of 3,5,6-trichloro-2-pyridinol (TCPy), a metabolite of CPF, into saliva after exposure to TCPy. The objective of this study was to quantitatively evaluatein vivopharmacokinetics and pharmacodynamics of CPF and TCPy in saliva after CPF administration. Rats were coadministered CPF (0.5–5mg/kg) and pilocarpine (~13mg/kg) iv. Saliva and blood were collected, and levels of CPF, TCPy, and cholinesterase (ChE) activity were quantified. Experimental results suggest that CPF is rapidly metabolized after iv administration. Formation of TCPy from administered CPF at the low dose (0.5mg/kg) was slower than from higher CPF doses, potentially due to differences in plasma protein binding to CPF. CPF was measured in saliva only at the first time point sampled (0–15min), indicating low partitioning and rapid metabolism. After formation, TCPy pharmacokinetics were very similar in blood and saliva. Saliva/blood TCPy concentration ratios were not affected by TCPy concentration in blood, saliva flow rate, or salivary pH and were consistent with previous studies. ChE activity in plasma demonstrated a dose-dependent decrease, and ChE activity in saliva was extremely variable and demonstrated no dose relationship. A physiologically based pharmacokinetic and pharmacodynamic model for CPF was modified and predicted the data reasonably well. It is envisioned that a combination of biomonitoring compounds like TCPy in saliva coupled with computational modeling will form an approach to measure pesticide exposure to susceptible human populations such as agricultural workers.