Quantitative prediction of CYP3A-mediated drug-drug interactions by correctly estimating fraction metabolized using...

Fraction metabolized (f_m ) and fraction transported (f_t ) are important for understanding drug-drug interactions (DDIs) in drug discovery and development. However, current in vitro systems cannot accurately estimate in vivo f_m due to inability to reflect the f_t by efflux transporters (f_t,efflux ). This study demonstrates how CYP3A-mediated DDI for CYP3A/P-gp substrates can be predicted using Hu-PXB mice as human liver chimeric mice.

For estimating human in vitro f_m by CYP3A enzyme (f_{m,CYP3A,in vitro} ), six drugs, including CYP3A/P-gp substrates (alprazolam, cyclosporine, docetaxel, midazolam, prednisolone, and theophylline) and human hepatocytes were incubated with or without ketoconazole as a CYP3A inhibitor. We calculated f_{m,CYP3A,in vitro} based on hepatic intrinsic clearance. To estimate human in vivo f_m,CYP3A (f_{m,CYP3A,in vivo} ), we collected information on clinical DDI caused by ketoconazole for these six drugs. We calculated f_{m,CYP3A,in vivo} using the change of total clearance (CL_total ). For evaluating the human DDI predictability, the six drugs were administered intravenously to Hu-PXB and SCID mice with or without ketoconazole. We calculated the change of CL_total caused by ketoconazole. We compared the CL_total change in humans with that in Hu-PXB and SCID mice.

The f_{m,CYP3A,in vitro} was overestimated compared to the f_{m,CYP3A,in vivo} . Hu-PXB mice showed much better correlation in the change of CL_total with humans (R²  = 0.95) compared to SCID mice (R²  = 0.0058).

CYP3A-mediated DDI can be predicted by correctly estimating human f_{m,CYP3A,in vivo} using Hu-PXB mice. These mice could be useful predicting hepatic f_m and f_t,efflux .