Quantitative prediction of drug disposition for uridine diphosphate-glucuronosyltransferase substrates using humanized mice.

Abstract

Drug clearance and drug-drug interactions are essential for pharmacokinetic assessment. However, current in vitro systems and animal scale-up approaches often fail to accurately predict drug disposition mediated by metabolizing enzymes, especially uridine diphosphate-glucuronosyltransferase (UGT). This study demonstrates how UGT-mediated drug disposition in humans can be predicted using hu-PXB mice (cDNA-uPA/severe combined immunodeficiency (SCID) mice transplanted with human-derived hepatocytes). To estimate human hepatic intrinsic clearance (CL_h,int) in vitro, UGT substrates (acetaminophen, entacapone, ketoprofen, lorazepam, oxazepam, posaconazole, and zidovudine) were incubated with cryopreserved human hepatocytes. CL_h,int was calculated based on the rate of substrate disappearance. In vivo human CL_h,int values were calculated based on literature. To evaluate human CL_h,int predictability, the 7 substrates were administered independently and intravenously to hu-PXB and SCID mice. We calculated the CL_h,int in the mice and compared it with that in humans. For predicting UGT-mediated drug-drug interactions, 2 UGT substrates were administered intravenously to hu-PXB mice with or without probenecid (a UGT inhibitor). We compared the changes in clearance with those in humans. The in vitro assay using hepatocytes significantly underpredicted CL_h,int in humans. Hu-PXB mice had a much better correlation with humans in CL_h,int (R² = 0.95) compared with SCID mice (R² = 0.69). Hu-PXB mice predicted the CL_h,int of UGT substrate drugs within 2-fold of the clinical values for every compound we evaluated. The decrease in clearance caused by probenecid in hu-PXB mice reflected that in humans. Our findings demonstrate that human drug disposition mediated by UGT can be predicted based on the in vivo studies using hu-PXB mice. SIGNIFICANCE STATEMENT: Human liver chimeric mice can accurately predict the clearance of uridine diphosphate-glucuronosyltransferase (UGT) substrate drugs and are likely to predict the magnitude of UGT-mediated drug-drug interactions. Findings from in vivo studies in humanized mice enable the selection of better candidates in drug discovery and allow for the more precise physiologically based pharmacokinetic modeling of UGT substrate drugs in clinical practice.