Accurately determine the hepatic intrinsic clearance of NCEs taking into account the active uptake into hepatocytes.

The hepatocyte uptake assay is in our portfolio of in vitro ADME services. We deliver consistent, high quality data with the flexibility to adapt protocols based on specific customer requirements.

Accurate measurement of hepatic uptake using the media loss method:

• Intrinsic clearance can be influenced by several processes including hepatic uptake, efflux, biliary excretion and drug metabolism².
• The predominant transporters involved in human hepatic uptake include OATPs, NTCP, OCTs and OATs³. These transporters determine intracellular concentrations which can influence clearance as well as potential DDI and hepatotoxicity.
• Inter-individual variability in hepatic uptake is also likely for substrates of hepatic uptake transporters which exhibit polymorphisms.
• Through its parent company, Evotec, Cyprotex is able to offer a hepatic uptake assay which utilizes the media loss⁴ approach, and determines the hepatic uptake intrinsic clearance.

_{1) Riley RJ et al., (2016) Hepatic drug transporters: the journey so far. Expert Opin Drug Metab Toxicol 12(2); 201-216
2) Maeda K and Sugiyama Y (2013) Prediction of hepatic transporter-mediated drug-drug interaction from in vitro data. In Transporters in Drug Development – Discovery, Optimization, Clinical Study and Regulation. Ed. Sugiyama Y and Steffansen B. 121-154
3) Annaert P et al (2007) Drug Transporters in the Liver. In Drug Transporters: Molecular Characterization and Role in Drug Disposition. Ed. You G and Morris ME. 359-410
4) Soars MG et al., (2007) Use of hepatocytes to assess the contribution of hepatic uptake to clearance in vivo. Drug Metab Dispos 35(6); 859-865
5) Ishiguro N et al., (2006) Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans. Drug Metab Dispos 34(7); 1109-1115
6) Paine SW et al., (2008) Prediction of the pharmacokinetics of atorvastatin, cerivastatin, and indomethacin using kinetic models applied to isolated rat hepatocytes. Drug Metab Dispos 36(7); 1365-1374
7) Gardiner P and Paine SW (2011) The impact of hepatic uptake on the pharmacokinetics of organic anions. Drug Metab Dispos 39(10); 1930-1938
8) Ménochet K et al., (2012) Use of mechanistic modelling to assess interindividual variability and interspecies differences in active uptake in human and rat hepatocytes. Drug Metab Dispos 40(9); 1744-1756
9) Ménochet K et al., (2012) Simultaneous assessment of uptake and metabolism in rat hepatocytes: a comprehensive mechanistic model. J Pharmacol Exp Ther 341(1); 2-15
10) Grime K and Riley RJ (2006) The impact of in vitro binding on in vitro-in vivo extrapolations, projections of metabolic clearance and clinical drug-drug interactions. Curr Drug Metab 7; 251-264
11) Hagenbuch B & Meier PJ (2003) The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 1609(1); 1-18}