Use of a Novel Cell-based Model to Predict Hepatic Clearance of Statins: In Vitro to In Vivo Correlation

Statins are a class of drugs targeting the liver to lower cholesterol levels by inhibiting HMG-CoA reductase activity. The clearance of statins is mainly directed by SLC transporter-mediated hepatic uptake, primarily by OATP1B1. Inhibition of OATP1B1 uptake activity leads to a significant increase in statin concentration in the blood, which can result in severe side effects. Because of their emerging clinical importance in drug absorption, disposition and elimination, the evaluation of several membrane transporters, including OATP1B1 as mediators of drug-drug interactions, has been recommended by regulatory agencies. One key question presented to drug development project teams is to identify suitable and predictive in vitro models to assess drug interactions with these transporters. In the present study, a newly developed cell-based model, Corning TransportoCells™ OATP1B1 cells, was used to characterize the intrinsic clearance of a series of statins. All statins showed significantly higher uptake in OATP1B1 cells compared with control cells. The kinetic parameters were determined for rosuvastatin, pravastatin, pitavastatin, simvastatin, atorvastatin, and fluvastatin. The intrinsic clearance rates showed high correlation with the apparent hepatic uptake clearance rates measured in cryopreserved human hepatocytes. The data demonstrate that TransportoCells products can be a useful tool to predict hepatic uptake clearance.