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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
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نویسنده
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peyret t. ,krishnan k.
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منبع
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journal of toxicology - 2012 - دوره : 2012 - شماره : 0
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چکیده
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The objectives of this study were (i) to develop a screening-level quantitative property-property relationship (qppr) for intrinsic clearance (c l int) 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. c l int,calculated as the ratio of the in vivo v max (mol/h/kg bw rat) to the k m (m),was obtained for 26 vocs from the literature. the qppr model resulting from stepwise linear regression analysis passed the validation step (r 2 = 0.8; leave-one-out cross-validation q 2 = 0.75) for c l int normalized to the phospholipid (pl) affinity of the vocs. the qppr facilitated the calculation of c l int (l pl/h/kg bw rat) from the input data on log p ow,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 c l int) to minimum (using umci for c l int) 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 c l int in predicting human pharmacokinetics of vocs,as well as the impact of prediction uncertainty of c l int on human pharmacokinetics of vocs. copyright © 2012 thomas peyret and kannan krishnan.
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آدرس
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département de santé environnementale et santé au travail,université de montréal,c.p. 6128,succursale centre-ville, Canada, département de santé environnementale et santé au travail,université de montréal,c.p. 6128,succursale centre-ville, Canada
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Authors
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