The ability to predict human liver-to-plasma unbound partition coefficient (Kpuu) 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 Kpuu 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 Kpuu 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 Kpuu values were mostly within 2-fold of in vivo Kpuu. Good Kpuu IVIVE in human was also observed with in vivo Kpuu data of dehydropravastatin from positron emission tomography and in vivo Kpuu data from PK/PD modeling for pravastatin and rosuvastatin. Under the specific Kpuu 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 Kpuu from in vitro data. The novel in vitro Kpuu method provides a useful tool in drug discovery to project in vivo Kpuu.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics