Quantitative Proteomics and Mechanistic Modeling of Transporter-mediated Disposition in Non-Alcoholic Fatty Liver Disease.Clin Pharmacol Ther 2019CP
Understanding transporter-mediated drug disposition and pharmacokinetics (PK) in patients with non-alcoholic fatty liver disease (NAFLD) is critical in developing treatment options. Here, we quantified the expression levels of major drug transporters in healthy, steatosis and non-alcoholic steatohepatitis (NASH) liver samples, via liquid-chromatography tandem mass spectrometry-based proteomics, and used the data to predict the PK of substrate drugs in the disease state. Expression of organic anion transporting polypeptides (OATPs) and multidrug resistance-associated protein (MRP)2 is significantly lower in NASH livers; whereas, MRP3 is induced while no change was observed for organic cation transporter (OCT)1. PBPK models verified with PK data from healthy subjects well recovered the PK in NASH subjects for morphine (involving OCT1) and its glucuronide metabolites (MRP2/MRP3/OATP1B), 99m TC-mebrofenen (OATP1B/MRP2/MRP3), and rosuvastatin (OATP1B/breast cancer resistance protein). Overall, considerations to altered protein expression can enable quantitative prediction of PK changes in subjects with NAFLD.