Quantitative prediction of OATP-mediated disposition and biliary clearance using human liver chimeric mice.

Drug biliary clearance (CL bile ) in vivo is among the most difficult pharmacokinetic parameters to predict accurately and quantitatively because biliary excretion is influenced by metabolic enzymes, transporters, and passive diffusion across hepatocyte membranes. The purpose of this study is to demonstrate the use of Hu-FRG{trade mark, serif} mice (Fah -/- /Rag2 -/- /Il2rg -/- [FRG] mice transplanted with human-derived hepatocytes) to quantitatively predict human organic-anion-transporting polypeptide (OATP)-mediated drug disposition and CL bile To predict OATP-mediated disposition, six OATP substrates (atorvastatin, fexofenadine, glibenclamide, pitavastatin, pravastatin, and rosuvastatin) were administered intravenously to Hu-FRG{trade mark, serif} and Mu-FRG{trade mark, serif} mice (FRG mice transplanted with mouse hepatocytes) with or without rifampicin as an OATP inhibitor. We calculated the hepatic intrinsic clearance (CL h,int ) and the change of hepatic clearance (CL h ) caused by rifampicin (CL h ratio). We compared the CL h,int of humans with that of Hu-FRG{trade mark, serif} mice, and the CL h ratio of humans with that of Hu-FRG{trade mark, serif} and Mu-FRG{trade mark, serif} mice. For predicting CL bile , twenty compounds (two cassette doses of ten compounds) were administered intravenously to gallbladder-cannulated Hu-FRG{trade mark, serif} and Mu-FRG{trade mark, serif} mice. We evaluated the CL bile and investigated the correlation of human CL bile with that of Hu-FRG and Mu-FRG mice. We found good correlations between humans and Hu-FRG{trade mark, serif} mice in CL h,int (100% within 3-fold) and CL h ratio (R 2 = 0.94). Moreover, we observed a much better relationship between humans and Hu-FRG{trade mark, serif} mice in CL bile (75% within 3-fold). Our results suggest that OATP-mediated disposition and CL bile can be predicted using Hu-FRG{trade mark, serif} mice, making them a useful in vivo drug discovery tool for quantitatively predicting human liver disposition. Significance Statement OATP-mediated disposition and biliary clearance of drugs are likely quantitatively predictable using Hu-FRG™ mice. The findings can enable the selection of better drug candidates and the development of more effective strategies for managing OATP-mediated DDI in clinical studies.