Quantitative structure–property relationships for physiologically based pharmacokinetic modeling of volatile organic chemicals in rats

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The objective of present study was to develop quantitative structure–property relationships (QSPRs) for the chemical-specific input parameters of rat physiologically based pharmacokinetic (PBPK) models (i.e., blood:air partition coefficient (Pb), liver:air partition coefficient (Pl), muscle:air partition coefficient (Pm), fat:air partition coefficient (Pf), and hepatic clearance (CLh)), for simulating the inhalation pharmacokinetics of volatile organic chemicals (VOCs). The literature data on Pb, Pl, Pf, and Pm for 46 low-molecular-weight VOCs as well as CLh for 25 such VOCs primarily metabolized by CYP2E1 (alkanes, haloalkanes, haloethylenes, and aromatic hydrocarbons) were analysed to develop QSPRs. The QSPRs developed in this study were essentially multilinear additive models, which imply that each fragment in the molecular structure has an additive and constant contribution to partition coefficients and hepatic clearance. Most of the values in the calibration set could be reproduced adequately with the QSPR approach, which involved the calculation of the sum of the frequency of occurrence of fragments (CH3, CH2, CH, C, C=C, H, Cl, Br, F, benzene ring, and H in benzene ring structure) times the fragment-specific contributions determined in this study. The QSPRs for Pb, Pl, Pm, Pf, and CLh were then included within a PBPK model, which only required the specification of the frequency of occurrence of fragments in a molecule along with exposure concentration and duration as input for conducting pharmacokinetic simulations. This QSPR–PBPK model framework facilitated the prediction of the inhalation pharmacokinetics of four VOCs present in the calibration dataset (toluene, dichloromethane, trichloroethylene, and 1,1,1-trichloroethane) and four VOCs that were not part of the calibration set (1,2,4-trimethyl benzene, ethyl benzene, 1,3-dichloropropene, and 2,2-dichloro-1,1,1-trifluoroethane) but that could be described using the molecular fragments investigated in the present study. The QSPRs developed in this study should be potentially useful for providing a first-cut evaluation of the inhalation pharmacokinetics of VOCs prior to experimentation, as long as the number and nature of the fragments do not exceed the ones in the calibration dataset used in this study.

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