A physiologically-based pharmacokinetic model of methotrexate incorporating hepatic excretion via multidrug-resistance-associated protein 2 (Mrp2) in mice, rats, dogs, and humans
| Autor: | Yasong Lu, Raymond S. H. Yang, Ornrat Lohitnavy, Manupat Lohitnavy |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Physiologically based pharmacokinetic modelling business.industry Multidrug resistance-associated protein 2 Pharmacology Rats Hepatobiliary Elimination 03 medical and health sciences Biliary excretion Mice 030104 developmental biology Dogs Methotrexate Pharmacokinetics Liver Hepatic Excretion Model simulation Medicine Animals Humans business medicine.drug |
| Zdroj: | EMBC |
| ISSN: | 2694-0604 |
| Popis: | An updated physiologically-based pharmacokinetic (PBPK) model of methotrexate (MTX) was built based on an earlier model developed by Bischoff et al. (1971). MTX has been known to be a substrate of multidrug-resistance-associated protein 2 (Mrp2). A three-dimensional quantitative structure-activity relationship model (3D-QSAR) of Mrp2 was developed by Hirono et al. (2005). In our updated PBPK model of MTX, using the computational chemistry-derived binding affinity (K m ), a Mrp2-mediated biliary excretion process was incorporated as the MTX excretory pathway. Our model simulation results are consistent with numerous datasets obtained from mice, rats, dogs, and humans, at a variety of dose levels. Comparisons were made between our updated PBPK model and the earlier one from Bischoff et al. using a PBPK Index approach. Our new PBPK model was further verified against additional pharmacokinetic datasets from rats under special experimental conditions (cannulated bile duct) and Eisai hyperbirilubinemic rats. |
| Databáze: | OpenAIRE |
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