Kamgang E, Peyret T, Krishnan K
Groupe de recherche interdisciplinaire en sante, Faculte de medecine, Universite de Montreal, Montreal, QC, Canada.
SAR QSAR Environ Res. 2008;19(7-8):669-80. doi: 10.1080/10629360802547313.
In vitro data on metabolism and partitioning may be integrated within physiologically-based pharmacokinetic (PBPK) models to provide simulations of the kinetics and bioaccumulation of chemicals in intact organisms. Quantitative structure-property relationship (QSPR) modelling of available in vitro data may be performed to predict metabolism rates and partition coefficients (PCs) for developing in vivo PBPK models. The objective of the present study was to develop an integrated QSPR-PBPK modelling approach for the conduct of in vitro to in vivo extrapolation. For this purpose, data on rat blood:air (P(b)) and fat:air (P(f)) PCs, as well as intrinsic metabolic clearance (CL(int)) obtained using rat liver slices for some C(5)-C(10) volatile organic compounds (VOCs) were compiled from the literature. Multilinear additive QSPR models for P(f), P(b) and CL(int) were developed based on the number and nature of molecular fragments in these VOCs (CH(3), CH(2), CH, C, C=C, H, benzene ring and H in benzene ring structure). The mean estimated/experimental (est/exp) ratios (+/-SD; range) were 1.0 (+/-0.04; 0.93 - 1.06) for log P(f), 1.08 (+/-0.26; 0.70 - 1.62) for log P(b), and 1.07 (+/- 0.21; 0.80 - 1.44) for CL(int). By accounting for the difference in the content of neutral lipids in fat and other tissues, the liver : air and muscle : air PCs of the compounds investigated in this study, with the excerption of n-decane, were adequately predicted from P(f). Integrating the QSPRs for P(f), P(b) and CL(int) within a rat PBPK model, simulations of inhalation pharmacokinetics of several VOCs were generated on the basis of molecular structure, for a given exposure scenario. The integrated QSPR-PBPK model developed in this study is a potentially useful tool for predicting in vivo kinetics and bioaccumulation of chemicals in rats under poor data situations.
关于代谢和分配的体外数据可整合到基于生理学的药代动力学（PBPK）模型中，以模拟完整生物体中化学物质的动力学和生物累积情况。可对现有体外数据进行定量结构-性质关系（QSPR）建模，以预测代谢率和分配系数（PCs），用于构建体内PBPK模型。本研究的目的是开发一种综合的QSPR-PBPK建模方法，用于进行体外到体内的外推。为此，从文献中收集了大鼠血液与空气（P(b)）和脂肪与空气（P(f)）的分配系数数据，以及使用大鼠肝切片获得的一些C(5)-C(10)挥发性有机化合物（VOCs）的内在代谢清除率（CL(int)）数据。基于这些VOCs（CH(3)、CH(2)、CH、C、C=C、H、苯环以及苯环结构中的H）分子片段的数量和性质，开发了P(f)、P(b)和CL(int)的多线性加和QSPR模型。log P(f)的平均估计值与实验值（est/exp）之比（±标准差；范围）为1.0（±0.04；0.93 - 1.06），log P(b)为1.08（±0.26；0.70 - 1.62），CL(int)为1.07（±0.21；0.80 - 1.44）。通过考虑脂肪和其他组织中中性脂质含量的差异，本研究中所研究化合物（除正癸烷外）的肝脏与空气和肌肉与空气的分配系数可根据P(f)进行充分预测。将P(f)、P(b)和CL(int)的QSPRs整合到大鼠PBPK模型中，基于分子结构，针对给定的暴露场景生成了几种VOCs吸入药代动力学的模拟结果。本研究开发的综合QSPR-PBPK模型是在数据匮乏情况下预测大鼠体内化学物质动力学和生物累积的潜在有用工具。
