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
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 o...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2012-01-01
|
| Series: | Journal of Toxicology |
| Online Access: | http://dx.doi.org/10.1155/2012/286079 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850163206291456000 |
|---|---|
| author | Thomas Peyret Kannan Krishnan |
| author_facet | Thomas Peyret Kannan Krishnan |
| author_sort | Thomas Peyret |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-eb816eb92c654534bf03fc0422fe6644 |
| institution | OA Journals |
| issn | 1687-8191 1687-8205 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Toxicology |
| spelling | doaj-art-eb816eb92c654534bf03fc0422fe66442025-08-20T02:22:20ZengWileyJournal of Toxicology1687-81911687-82052012-01-01201210.1155/2012/286079286079Quantitative 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 HumansThomas Peyret0Kannan Krishnan1Département de Santé Environnementale et Santé au Travail, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, CanadaDépartement de Santé Environnementale et Santé au Travail, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, CanadaThe 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.http://dx.doi.org/10.1155/2012/286079 |
| spellingShingle | Thomas Peyret Kannan Krishnan 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://dx.doi.org/10.1155/2012/286079 |
| work_keys_str_mv | AT thomaspeyret quantitativepropertypropertyrelationshipforscreeninglevelpredictionofintrinsicclearanceofvolatileorganicchemicalsinratsanditsintegrationwithinpbpkmodelstopredictinhalationpharmacokineticsinhumans AT kannankrishnan quantitativepropertypropertyrelationshipforscreeninglevelpredictionofintrinsicclearanceofvolatileorganicchemicalsinratsanditsintegrationwithinpbpkmodelstopredictinhalationpharmacokineticsinhumans |