Nonalcoholic steatohepatitis increases plasma retention of sorafenib-glucuronide in a mouse model by altering hepatocyte hopping  

作　　者：Erica Toth Hui Li Kayla Frost Paxton Sample Joseph Jilek Siennah Greenfield Dahea You Danielle Kozlosky Michael Goedken Mary F.Paine Lauren Aleksunes Nathan Cherrington 

机构地区：[1]University of Arizona,Tucson,AZ 85721,USA [2]Rutgers University,Piscataway,NJ 08854,USA [3]Washington State University,Spokane,WA 99202,USA

出　　处：《Acta Pharmaceutica Sinica B》2024年第11期4874-4882,共9页药学学报（英文版）

基　　金：by National Institute of General Medical Sciences grant(GM123643,USA);National Institute of Environmental Health Sciences grants(T32ES007148,ES028668,ES006694,and ES007091,USA).

摘　　要：Hepatocyte hopping is the hepatocyte-to-sinusoid-to-hepatocyte shuttling that increases the efficiency of hepatic elimination of xenobiotics. This phenomenon is mediated via efflux of hepatic metabolites by Mrp3 and reuptake by Oatp transporters in sequential hepatocytes until eventual biliary efflux by Mrp2. Sorafenib-glucuronide (SFB-G), the major metabolite of sorafenib (SFB), undergoes hepatocyte hopping, leading to efficient biliary elimination. Nonalcoholic steatohepatitis (NASH) alters the functioning of transporters involved in hepatocyte hopping. The purpose of this study was to quantify the effect of NASH on the three drug disposition processes of hepatocyte hopping. Male FVB and C57BL/6 wild-type (WT), Oatp1a/1b cluster knockout (O^(−/−)), and Mrp2 knockout (Mrp2^(−/−)) mice were fed a methionine and choline deficient (MCD) diet to induce NASH. Mice were administered 10 mg/kg SFB via oral gavage and concentrations of SFB and SFB-G in plasma quantified using liquid-chromatography tandem mass spectrometry. Compared to WT, plasma area under the concentration-time curve (AUC) of SFB-G increased by 108-fold in the O^(-/--)C group and by 345-fold in the Mrp2^(-/--)C group. In the WT-NASH group, up-regulation of Mrp3 and decreased Mrp2 function, along with reduced Oatp uptake, elevated SFB-G AUC by 165-fold. SFB-G AUC in the O^(-/--)NASH group increased by 108-fold compared to WT-C (3.2-fold compared to O^(-/--)C). SFB-G AUC in the Mrp2^(-/--)NASH group increased by 450-fold (1.2-fold compared to Mrp2^(-/--)C). Taken together, the mislocalization of Mrp2 in NASH is a major contributor to the decrease in SFB-G biliary efflux, but decreased Oatp uptake and enhanced sinusoidal efflux also limit the contribution of downstream hepatocytes, resulting in plasma retention that recapitulates the altered pharmacokinetics observed in human NASH.

关 键 词：Nonalcoholic steatohepatitis Hepatocytehopping SORAFENIB Sorafenibglucuronide Drug disposition ADME Transport Knockoutmouse 

分 类 号：R575.5[医药卫生—消化系统]