Hepatic Organic Anion Transporting Polypeptide–Mediated Clearance in the Beagle Dog: Assessing In Vitro–In Vivo Relationships and Applying Cross-Species Empirical Scaling Factors to Improve Prediction of Human Clearance

In the present study, the beagle dog was evaluated as a preclinical model to investigate organic anion transporting polypeptide (OATP)–mediated hepatic clearance. In vitro studies were performed with nine OATP substrates in three lots of plated male dog hepatocytes ± OATP inhibitor cocktail to determine total uptake clearance (CL uptake ) and total and unbound cell-to-medium concentration ratio (Kp uu ). In vivo intrinsic hepatic clearances (CL int,H ) were determined following intravenous drug administration (0.1 mg/kg) in male beagle dogs. The in vitro parameters were compared with those previously reported in plated human, monkey, and rat hepatocytes; the ability of cross-species scaling factors to improve prediction of human in vivo clearance was assessed. CL uptake in dog hepatocytes ranged from 9.4 to 135 µ l/min/10 6 cells for fexofenadine and telmisartan, respectively. Active process contributed >75% to CL uptake for 5/9 drugs. Rosuvastatin and valsartan showed Kp uu > 10, whereas cerivastatin, pitavastatin, repaglinide, and telmisartan had Kp uu int,H was applied as an average empirical scaling factor (ESF av ) for in vitro–in vivo extrapolation of human CL int,H . The ESF av based on dog reduced underprediction of human CL int,H for the same data set (geometric mean fold error = 2.1), highlighting its utility as a preclinical model to investigate OATP-mediated uptake. The ESF av from all preclinical species resulted in comparable improvement of human clearance prediction, in contrast to drug-specific empirical scalars, rationalized by species differences in expression and/or relative contribution of particular transporters to drug hepatic uptake.