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Journal of Toxicology
Volume 2012, Article ID 286079, 22 pages
Research Article

Quantitative Property-Property Relationship for Screening-Level Prediction of Intrinsic Clearance of Volatile Organic Chemicals in Rats and Its Integration within PBPK Models to Predict Inhalation Pharmacokinetics in Humans

Département de Santé Environnementale et Santé au Travail, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, Canada H3C 3J7

Received 31 October 2011; Revised 13 January 2012; Accepted 13 January 2012

Academic Editor: Jane C. Caldwell

Copyright © 2012 Thomas Peyret and Kannan Krishnan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The objectives of this study were (i) to develop a screening-level Quantitative property-property relationship (QPPR) for intrinsic clearance (CLint) obtained from in vivo animal studies and (ii) to incorporate it with human physiology in a PBPK model for predicting the inhalation pharmacokinetics of VOCs. CLint, calculated as the ratio of the in vivo Vmax (μmol/h/kg bw rat) to the Km (μM), was obtained for 26 VOCs from the literature. The QPPR model resulting from stepwise linear regression analysis passed the validation step (R2=0.8; leave-one-out cross-validation Q2=0.75) for CLint normalized to the phospholipid (PL) affinity of the VOCs. The QPPR facilitated the calculation of CLint (L PL/h/kg bw rat) from the input data on log Pow, log blood: water PC and ionization potential. The predictions of the QPPR as lower and upper bounds of the 95% mean confidence intervals (LMCI and UMCI, resp.) were then integrated within a human PBPK model. The ratio of the maximum (using LMCI for CLint) to minimum (using UMCI for CLint) AUC predicted by the QPPR-PBPK model was 1.36±0.4 and ranged from 1.06 (1,1-dichloroethylene) to 2.8 (isoprene). Overall, the integrated QPPR-PBPK modeling method developed in this study is a pragmatic way of characterizing the impact of the lack of knowledge of CLint in predicting human pharmacokinetics of VOCs, as well as the impact of prediction uncertainty of CLint on human pharmacokinetics of VOCs.