Comparison of the Predictability of Human Hepatic Clearance for Organic Anion Transporting Polypeptide Substrate Drugs Between Different In Vitro-In Vivo Extrapolation Approaches

J Pharm Sci. 2017 Sep;106(9):2678-2687. doi: 10.1016/j.xphs.2017.02.012. Epub 2017 Feb 24.


Prediction of human pharmacokinetic profiles of drug candidates is an essential step toward first-in-human studies. However, it remains difficult to quantitatively predict hepatic clearance, particularly when hepatic uptake is mediated by transporter(s). Using 15 organic anion transporting polypeptide (OATP) substrate drugs, we tested 3 in vitro-in vivo extrapolation (IVIVE) approaches to predict overall hepatic intrinsic clearance in vivo (CLint,all,vivo). IVIVE approaches involved metabolic intrinsic clearance in human liver microsomes (CLint,met) with or without hepatocyte-to-buffer maximum unbound concentration ratio (Kp,uu,max) correction and uptake intrinsic clearance at 37°C (PSinf,37°C) in human hepatocyte suspensions. Kp,uu,max and PSinf,37°C values were determined in 2 hepatocyte batches, and all tested compounds showed temperature-dependent uptake, consistent with the fact of transporter-mediated uptake. CLint,met substantially underestimated CLint,all,vivo. By multiplying CLint,met by Kp,uu,max values, the prediction performance was much improved; however, in vitro-in vivo correlation was poor. Among the IVIVE approaches, PSinf,37°C showed the most robust correlation with CLint,all,vivo, and one of the hepatocyte batches could predict CLint,all,vivo with a minimal empirical scaling factor. These results suggested IVIVE with hepatic uptake clearance determined in hepatocyte suspensions as one of the most practical approaches for predicting CLint,all,vivo of OATP substrate drugs.

Keywords: active transport; cytochrome P450; glucuronosyltransferase (UGT); hepatic clearance; hepatic transport; hepatocytes; membrane transport/transporters; organic anion transporting polypeptide transporters; transporters.

Publication types

  • Comparative Study

MeSH terms

  • Biological Transport
  • Glucuronosyltransferase / metabolism
  • Hepatocytes
  • Humans
  • Kinetics
  • Liver / metabolism*
  • Metabolic Clearance Rate
  • Microsomes, Liver / metabolism*
  • Models, Biological*
  • Organic Anion Transporters / metabolism*
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Binding
  • Tandem Mass Spectrometry / methods
  • Temperature


  • Organic Anion Transporters
  • Peptides
  • Glucuronosyltransferase