Novel Method to Predict In Vivo Liver-to-Plasma Kpuu for OATP Substrates Using Suspension Hepatocytes

Abstract

The ability to predict human liver-to-plasma unbound partition coefficient (K_puu) is of great importance to estimate unbound liver concentration, develop PK/PD relationships, predict efficacy and toxicity in the liver, and model the drug-drug interaction potential for drugs that are asymmetrically distributed into the liver. A novel in vitro method has been developed to predict in vivo K_puu with good accuracy using cryopreserved suspension hepatocytes in InVitroGRO HI media with 4% BSA. Validation was performed using six OATP substrates with rat in vivo K_puu data from i.v. infusion studies where a steady state was achieved. Good in vitro-in vivo correlation (IVIVE) was observed as the in vitro K_puu values were mostly within 2-fold of in vivo K_puu Good K_puu IVIVE in human was also observed with in vivo K_puu data of dehydropravastatin from positron emission tomography and in vivo K_puu data from PK/PD modeling for pravastatin and rosuvastatin. Under the specific K_puu assay conditions, the drug-metabolizing enzymes and influx/efflux transporters appear to function at physiologic levels. No scaling factors are necessary to predict in vivo K_puu from in vitro data. The novel in vitro K_puu method provides a useful tool in drug discovery to project in vivo K_puu.