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
| Autor: | Kathleen M. Hillgren, David W. Bedwell, Bridget L. Morse, Norikazu Matsunaga, Aleksandra Galetin, Michael A. Mohutsky, J. Brian Houston, Stephen D. Hall, Jingqi Bao, Ayşe Ufuk |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
Liver cytology Metabolic Clearance Rate Drug Evaluation Preclinical Pharmaceutical Science Organic Anion Transporters Pharmacology 030226 pharmacology & pharmacy Beagle Models Biological 03 medical and health sciences 0302 clinical medicine Dogs Species Specificity In vivo medicine Animals Humans Pitavastatin Infusions Intravenous biology Chemistry Cerivastatin Repaglinide Organic anion-transporting polypeptide Liver Pharmaceutical Preparations 030220 oncology & carcinogenesis Models Animal biology.protein Hepatocytes Telmisartan medicine.drug |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 47(3) |
| ISSN: | 1521-009X |
| Popis: | 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 (CLuptake) and total and unbound cell-to-medium concentration ratio (Kpuu). In vivo intrinsic hepatic clearances (CLint,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. CLuptake in dog hepatocytes ranged from 9.4 to 135 µl/min/106 cells for fexofenadine and telmisartan, respectively. Active process contributed >75% to CLuptake for 5/9 drugs. Rosuvastatin and valsartan showed Kpuu > 10, whereas cerivastatin, pitavastatin, repaglinide, and telmisartan had Kpuu < 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 CLint,H was applied as an average empirical scaling factor (ESFav) for in vitro-in vivo extrapolation of human CLint,H The ESFav based on dog reduced underprediction of human CLint,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 ESFav 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|