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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
Joint Authors
Krishnan, Kannan
Peyret, Thomas
Source
Issue
Vol. 2012, Issue 2012 (31 Dec. 2012), pp.1-22, 22 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2012-05-22
Country of Publication
Egypt
No. of Pages
22
Main Subjects
Pharmacy, Health & Medical Sciences
Medicine
Abstract EN
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.
American Psychological Association (APA)
Peyret, Thomas& Krishnan, Kannan. 2012. 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. Journal of Toxicology،Vol. 2012, no. 2012, pp.1-22.
https://search.emarefa.net/detail/BIM-460442
Modern Language Association (MLA)
Peyret, Thomas& Krishnan, Kannan. 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. Journal of Toxicology No. 2012 (2012), pp.1-22.
https://search.emarefa.net/detail/BIM-460442
American Medical Association (AMA)
Peyret, Thomas& Krishnan, Kannan. 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. Journal of Toxicology. 2012. Vol. 2012, no. 2012, pp.1-22.
https://search.emarefa.net/detail/BIM-460442
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-460442