Identification, Ki determination and CoMFA analysis of nuclear receptor ligands as competitive inhibitors of OATP1B1-mediated estradiol-17beta-glucuronide transport

Pharmacol Res. 2009 Jul;60(1):50-6. doi: 10.1016/j.phrs.2009.03.004. Epub 2009 Mar 17.


Evidence shows that drug-drug interactions can occur at the level of drug transporters such as the organic anion transporting polypeptides (OATPs), a group of membrane solute carriers that mediate the sodium-independent transport of a wide range of amphipathic organic compounds. The polyspecific OATP1B1 is exclusively expressed at the basolateral membrane of hepatocytes and mediates uptake of amphipathic organic compounds from blood into hepatocytes. Nuclear receptors are ligand-activated transcription factors that play an important role in xenobiotic disposition and human diseases. Quite a few nuclear receptor ligands interact with transport proteins. A high-resolution three-dimensional structure is critical to understand the polyspecificity of OATP1B1 to predict and prevent adverse drug-drug interactions. Unfortunately there are no crystal structures of OATPs/Oatps available to date. Therefore, in this study we attempted to elucidate the characteristics of the substrate binding site of OATP1B1 based on small molecules interacting with it. First, we identified inhibitors of the OATP1B1 model substrate estradiol-17beta-glucuronide from about 40 nuclear receptor ligands. Among them, GW1929, paclitaxel and troglitazone were strong inhibitors, while 5 alpha-androstane, 5 alpha-androstane-3beta, 17beta-diol-17-hexahydrobenzoate and estradiol-3-benzoate were weak inhibitors. Then, we selected 25 compounds and performed inhibition kinetic studies to identify competitive inhibitors and determine their K(i) values which ranged from submicromolar to submillimolar. Finally, we performed CoMFA analysis on the identified competitive inhibitors. The CoMFA results indicate that the substrate binding site of OATP1B1 consists of a large hydrophobic middle part with basic residues at both ends that could be very important for substrate binding.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Drug Interactions
  • Energy Transfer
  • Estradiol / analogs & derivatives*
  • Estradiol / chemistry
  • Estradiol / metabolism
  • Humans
  • Ligands
  • Liver-Specific Organic Anion Transporter 1
  • Models, Chemical*
  • Organic Anion Transporters / biosynthesis
  • Organic Anion Transporters / chemistry
  • Organic Anion Transporters / metabolism*
  • Protein Transport
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Transfection


  • Ligands
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • Receptors, Cytoplasmic and Nuclear
  • SLCO1B1 protein, human
  • Small Molecule Libraries
  • estradiol-17 beta-glucuronide
  • Estradiol