Development of a fluorescence-based assay for screening of modulators of human organic anion transporter 1B3 (OATP1B3)

Eur J Pharm Biopharm. 2006 Jan;62(1):39-43. doi: 10.1016/j.ejpb.2005.06.001. Epub 2005 Aug 29.

Abstract

The organic anion transporting protein 1B3 (OATP1B3), formerly termed OATP8, is responsible for uptake and subsequent elimination of multiple amphipathic drugs by the liver. In silico methods for the prediction of transport rates for drugs and drug-like molecules might provide an important tool in drug development. Most prediction methods however require a large training set of in vitro experimental data in order to yield reliable results. To obtain these data, we have developed a fluorescence-based assay that allows screening a relatively high number of substances for their transporter affinity. HEK293 cells overexpressing OATP1B3 (HEK-OATP8) [Y. Cui, J. Konig, D. Keppler, Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2, Mol. Pharmacol. 60 (2001) 934-943.] were tested for transport of Fluo-3. Fluo-3 uptake could be seen in a concentration-dependent manner. Uptake can be inhibited completely by the addition of the known OATP1B3-inhibitor rifampicin proving that Fluo-3 is transported by OATP1B3. To verify the suitability of the system to identify modulators of OATP1B3, we tested known substrates for competitively inhibiting the Fluo-3 transport by giving them simultaneously with a 2muM Fluo-3-solution to the cells. The transport of Fluo-3 was decreased by all test substrates in a concentration dependent manner.

MeSH terms

  • Aniline Compounds / metabolism*
  • Cell Line
  • Drug Evaluation, Preclinical / methods
  • Fluorescent Dyes / metabolism*
  • Humans
  • Inhibitory Concentration 50
  • Ketoconazole / pharmacology
  • Multidrug Resistance-Associated Protein 2
  • Organic Anion Transporters, Sodium-Independent / antagonists & inhibitors
  • Organic Anion Transporters, Sodium-Independent / genetics
  • Organic Anion Transporters, Sodium-Independent / metabolism*
  • Ouabain / pharmacology
  • Rifampin / pharmacology
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Transfection
  • Xanthenes / metabolism*

Substances

  • ABCC2 protein, human
  • Aniline Compounds
  • Fluorescent Dyes
  • Multidrug Resistance-Associated Protein 2
  • Organic Anion Transporters, Sodium-Independent
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Xanthenes
  • Fluo-3
  • Ouabain
  • Ketoconazole
  • Rifampin