Nong Andy, Tan Yu-Mei, Krolski Michael E, Wang Jiansuo, Lunchick Curt, Conolly Rory B, Clewell Harvey J
The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA.
J Toxicol Environ Health A. 2008;71(20):1363-81. doi: 10.1080/15287390802271608.
Carbaryl, an N-methyl carbamate (NMC), is a common insecticide that reversibly inhibits neuronal cholinesterase activity. The objective of this work was to use a hierarchical Bayesian approach to estimate the parameters in a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model from experimental measurements of carbaryl in rats. A PBPK/PD model was developed to describe the tissue dosimetry of carbaryl and its metabolites (1-naphthol and "other hydroxylated metabolites") and subsequently to predict the carbaryl-induced inhibition of cholinesterase activity, in particular in the brain and blood. In support of the model parameterization, kinetic tracer studies were undertaken to determine total radioactive tissue levels of carbaryl and metabolites in rats exposed by oral or intravenous routes at doses ranging from 0.8 to 9.2 mg/kg body weight. Inhibition of cholinesterase activity in blood and brain was also measured from the exposed rats. Markov Chain Monte Carlo (MCMC) calibration of the rat model parameters was implemented using prior information from literature for physiological parameter distributions together with kinetic and inhibition data on carbaryl. The posterior estimates of the parameters displayed at most a twofold deviation from the mean. Monte Carlo simulations of the PBPK/PD model with the posterior distribution estimates predicted a 95% credible interval of tissue doses for carbaryl and 1-naphthol within the range of observed data. Similar prediction results were achieved for cholinesterase inhibition by carbaryl. This initial model will be used to determine the experimental studies that may provide the highest added value for model refinement. The Bayesian PBPK/PD modeling approach developed here will serve as a prototype for developing mechanism-based risk models for the other NMCs.
西维因是一种N - 甲基氨基甲酸酯（NMC），是一种常见的杀虫剂，可可逆地抑制神经元胆碱酯酶活性。这项工作的目的是使用分层贝叶斯方法，根据大鼠体内西维因的实验测量值来估计基于生理学的药代动力学和药效学（PBPK/PD）模型中的参数。开发了一个PBPK/PD模型来描述西维因及其代谢物（1 - 萘酚和“其他羟基化代谢物”）的组织剂量学，并随后预测西维因诱导的胆碱酯酶活性抑制，特别是在脑和血液中的抑制。为支持模型参数化，进行了动力学示踪研究，以确定口服或静脉途径暴露于0.8至9.2 mg/kg体重剂量的大鼠体内西维因和代谢物的总放射性组织水平。还测量了暴露大鼠血液和脑中胆碱酯酶活性抑制情况。利用文献中关于生理参数分布的先验信息以及西维因的动力学和抑制数据，对大鼠模型参数进行马尔可夫链蒙特卡罗（MCMC）校准。参数的后验估计与均值的偏差至多为两倍。使用后验分布估计对PBPK/PD模型进行蒙特卡罗模拟，预测了西维因和1 - 萘酚组织剂量的95%可信区间在观测数据范围内。西维因对胆碱酯酶抑制的预测结果相似。这个初始模型将用于确定可能为模型优化提供最高附加值的实验研究。这里开发的贝叶斯PBPK/PD建模方法将作为开发其他NMC基于机制的风险模型的原型。
