Hepatic OATP-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

Research output: Contribution to journalArticle

  • External authors:
  • Norikazu Matsunaga
  • Ayse Ufuk
  • Bridget L Morse
  • David W Bedwell
  • Jingqi Bao
  • Michael A Mohutsky
  • Kathleen M Hillgren
  • Stephen D Hall

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 (CLuptake), 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 to 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 9.4-135 μL/min/106cells 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 vs. in vivo dog CLint,H was applied as an average empirical scaling factor (ESF av) for in vitro-in vivo extrapolation of human CLint,H. The ESF av based on dog reduced under-prediction of human CLint,H for the same dataset (gmfe=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.

Bibliographical metadata

Original languageEnglish
JournalDrug Metabolism and Disposition
Early online date28 Dec 2018
DOIs
Publication statusPublished - 2018

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