@article {LyDMD-AR-2021-000439, author = {Justin Q. Ly and Susan Wong and Liling Liu and Ruina Li and Kirsten Messick and Jae H. Chang}, title = {Investigating the Utility of Humanized PXR-CAR-CYP3A4/7 Mouse Model to Assess CYP3A-Mediated Induction}, elocation-id = {DMD-AR-2021-000439}, year = {2021}, doi = {10.1124/dmd.121.000439}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Clinical induction liability is assessed with human hepatocytes. However, underpredictions in the magnitude of clinical induction have been reported. Unfortunately, in vivo studies in animals do not provide additional insight due to species differences in drug metabolizing enzymes and their regulatory pathways. To circumvent this limitation, transgenic animals expressing human orthologues were developed. The aim of this work was to investigate the utility of mouse model expressing human orthologues of PXR, CAR and CYP3A4/7 (Tg-Composite) in evaluating clinical induction. Rifampin, efavirenz and pioglitazone, which were employed to represent strong, moderate and weak inducers, were administered at multiple doses to Tg-Composite animals. In vivo CYP3A activity was monitored by measuring changes in the exposure of the CYP3A probe substrate triazolam. Following the in vivo studies, microsomes were prepared from their livers to measure changes of in vitro CYP3A4 activity. In both in vivo and in vitro, distinction of clinic induction was recapitulated as rifampin yielded the greatest inductive effect following by efavirenz and pioglitazone. Interestingly, with rifampin, in vivo CYP3A activity was approximately 4-fold higher than in vitro activity. Conversely, there was no difference between in vivo and in vitro CYP3A activity with efavirenz. These findings are consistent with the report that while rifampin exhibits differential inductive effect between the intestines and liver, efavirenz does not. These data highlight the promise of transgenic models such as Tg-Composite to complement human hepatocytes to enhance the translatability of clinical induction as well as a powerful tool to further study mechanism of drug disposition. Significance Statement Underprediction of the magnitude of clinical induction when using human hepatocytes have been reported, and transgenic models may improve clinical translatability. The work presented here showcases the Tg-Composite model which was able to recapitulate the magnitude of clinical induction and to differentiate tissue dependent induction observed with rifampin, but not with efavirenz. These results not only foreshadow the potential application of such transgenic models in assessing clinical induction, but also in further investigating the mechanism of drug disposition.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2021/04/15/dmd.121.000439}, eprint = {https://dmd.aspetjournals.org/content/early/2021/04/15/dmd.121.000439.full.pdf}, journal = {Drug Metabolism and Disposition} }