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

Abstract

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 µl/min/10⁶ 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 < 5. The extent of hepatocellular binding in dog was consistent with other preclinical species and humans. The bias (2.73-fold) obtained from comparison of predicted versus in vivo dog CL_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.