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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.
Drug Metab Dispos 2019; 47(3):215-226DM

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 (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.

Authors+Show Affiliations

Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (N.M., A.U., J.B.H., A.G.); Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan (N.M.); and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (B.L.M., D.W.B., J.B., M.A.M., K.M.H., S.D.H.).Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (N.M., A.U., J.B.H., A.G.); Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan (N.M.); and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (B.L.M., D.W.B., J.B., M.A.M., K.M.H., S.D.H.).Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (N.M., A.U., J.B.H., A.G.); Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan (N.M.); and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (B.L.M., D.W.B., J.B., M.A.M., K.M.H., S.D.H.).Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (N.M., A.U., J.B.H., A.G.); Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan (N.M.); and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (B.L.M., D.W.B., J.B., M.A.M., K.M.H., S.D.H.).Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (N.M., A.U., J.B.H., A.G.); Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan (N.M.); and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (B.L.M., D.W.B., J.B., M.A.M., K.M.H., S.D.H.).Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (N.M., A.U., J.B.H., A.G.); Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan (N.M.); and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (B.L.M., D.W.B., J.B., M.A.M., K.M.H., S.D.H.).Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (N.M., A.U., J.B.H., A.G.); Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan (N.M.); and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (B.L.M., D.W.B., J.B., M.A.M., K.M.H., S.D.H.).Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (N.M., A.U., J.B.H., A.G.); Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan (N.M.); and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (B.L.M., D.W.B., J.B., M.A.M., K.M.H., S.D.H.).Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (N.M., A.U., J.B.H., A.G.); Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan (N.M.); and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (B.L.M., D.W.B., J.B., M.A.M., K.M.H., S.D.H.).Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (N.M., A.U., J.B.H., A.G.); Pharmacokinetic Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan (N.M.); and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (B.L.M., D.W.B., J.B., M.A.M., K.M.H., S.D.H.) Aleksandra.Galetin@manchester.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30593544

Citation

Matsunaga, Norikazu, et al. "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." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 47, no. 3, 2019, pp. 215-226.
Matsunaga N, Ufuk A, Morse BL, et al. 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. Drug Metab Dispos. 2019;47(3):215-226.
Matsunaga, N., Ufuk, A., Morse, B. L., Bedwell, D. W., Bao, J., Mohutsky, M. A., ... Galetin, A. (2019). 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. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 47(3), pp. 215-226. doi:10.1124/dmd.118.084194.
Matsunaga N, et al. 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. Drug Metab Dispos. 2019;47(3):215-226. PubMed PMID: 30593544.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Matsunaga,Norikazu, AU - Ufuk,Ayşe, AU - Morse,Bridget L, AU - Bedwell,David W, AU - Bao,Jingqi, AU - Mohutsky,Michael A, AU - Hillgren,Kathleen M, AU - Hall,Stephen D, AU - Houston,J Brian, AU - Galetin,Aleksandra, Y1 - 2018/12/28/ PY - 2018/08/24/received PY - 2018/12/17/accepted PY - 2018/12/30/pubmed PY - 2019/8/28/medline PY - 2018/12/30/entrez SP - 215 EP - 226 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 47 IS - 3 N2 - 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. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/30593544/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 L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=30593544 DB - PRIME DP - Unbound Medicine ER -