Battelle Memorial Institute, Pacific Northwest Division, Richland, Washington 99354, USA.
Toxicol Sci. 2010 Feb;113(2):315-25. doi: 10.1093/toxsci/kfp283. Epub 2009 Nov 17.
Biological monitoring (biomonitoring) to quantify systemic exposure to the organophosphorus insecticide chlorpyrifos (CPF) has historically focused on the quantitation of major CPF metabolites in urine. Noninvasive techniques are being advocated as novel means of biomonitoring for a variety of potential toxicants, including pesticides (like CPF), and saliva has been suggested as an ideal body fluid. However, in order to be acceptable, there is a need to understand salivary pharmacokinetics of CPF metabolites in order to extrapolate saliva measurements to whole-body exposures. In this context, in vivo pharmacokinetics of 3,5,6-trichloro-2-pyridinol (TCPy), the major chemical-specific metabolite of CPF, was quantitatively evaluated in rat saliva. Experimental results suggest that TCPy partitioning from plasma to saliva in rats is relatively constant over a range of varying physiological conditions. TCPy pharmacokinetics was very similar in blood and saliva (area under the curve values were proportional and elimination rates ranged from 0.007 to 0.019 per hour), and saliva/blood TCPy concentration ratios were not affected by TCPy concentration in blood (p = 0.35) or saliva flow rate (p = 0.26). The TCPy concentration in saliva was highly correlated to the amount of unbound TCPy in plasma (r = 0.96), and the amount of TCPy protein binding in plasma was substantial (98.5%). The median saliva/blood concentration ratio (0.049) was integrated as a saliva/blood TCPy partitioning coefficient within an existing physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for CPF. The model was capable of accurately predicting TCPy concentrations in saliva over a range of blood concentrations. These studies suggest that saliva TCPy concentration can be utilized to ascertain CPF exposure. It is envisioned that the PBPK/PD can likewise be used to estimate CPF dosimetry based on the quantitation of TCPy in spot saliva samples obtained from biomonitoring studies.
生物监测（生物监测）用于量化有机磷杀虫剂氯吡硫磷（CPF）的全身暴露，历史上一直侧重于尿液中 CPF 主要代谢物的定量。非侵入性技术被提倡作为各种潜在毒物（包括杀虫剂（如 CPF））生物监测的新方法，唾液被认为是一种理想的体液。然而，为了被接受，有必要了解 CPF 代谢物在唾液中的药代动力学，以便将唾液测量值外推到全身暴露。在这种情况下，在大鼠唾液中定量评估了 CPF 的主要化学特异性代谢物 3,5,6-三氯-2-吡啶醇（TCPy）的体内药代动力学。实验结果表明，TCPy 在大鼠血浆到唾液中的分配在一系列变化的生理条件下相对恒定。TCPy 的药代动力学在血液和唾液中非常相似（曲线下面积值成比例，消除率范围为 0.007 至 0.019 每小时），并且唾液/血液 TCPy 浓度比不受血液中 TCPy 浓度（p = 0.35）或唾液流速（p = 0.26）的影响。唾液中 TCPy 的浓度与血浆中未结合 TCPy 的量高度相关（r = 0.96），并且血浆中 TCPy 的蛋白结合量很大（98.5%）。中位数唾液/血液浓度比（0.049）作为 CPF 生理基于药代动力学和药效学（PBPK/PD）模型中的唾液/血液 TCPy 分配系数进行了整合。该模型能够准确预测血液浓度范围内唾液中 TCPy 的浓度。这些研究表明，唾液 TCPy 浓度可用于确定 CPF 暴露。预计 PBPK/PD 同样可以用于根据从生物监测研究中获得的点唾液样本中 TCPy 的定量来估计 CPF 剂量。
