Prediction of the in vivo OATP1B1-mediated drug-drug interaction potential of an investigational drug against a range of statins

Eur J Pharm Sci. 2012 Aug 30;47(1):244-55. doi: 10.1016/j.ejps.2012.04.003. Epub 2012 Apr 19.


To support drug development, the drug-drug interaction potential (DDI) of an investigational drug (AZX) was assessed against the probe estradiol 17β-glucuronide as well as against simvastatin acid, atorvastatin, pravastatin, pitavastatin, fluvastatin, rosuvastatin and estrone 3-sulfate. The inhibitory potentials of the OATP1B1 inhibitors rifamycin SV and gemfibrozil were assessed in parallel. Monolayer cellular uptake assays were used to determine inhibition of human OATP1B1. Apparent K(m) values for the OATP1B1-mediated transport of [(3)H] substrates were determined prior to their use as probes in inhibition studies, and ranged from 0.6 to 29 μM for statins. The K(m) of lipophilic simvastatin acid could not be determined due to its high passive permeability that masked OATP1B1 transport, and therefore this statin could not be used as a probe. Estrone 3-sulfate exhibited biphasic kinetics, whereas estradiol 17β-glucuronide demonstrated simple Michaelis-Menton kinetics. AZX moderately inhibited OATP1B1-mediated transport of all statins (IC(50)=4.6-9.7 μM), except fluvastatin, of estradiol 17β-glucuronide (IC(50)=5.3 μM), and weakly inhibited estrone 3-sulfate (IC(50)=79 μM). Rifamycin SV strongly, and gemfibrozil weakly, inhibited the OATP1B1-mediated transport of substrates. Estradiol 17β-glucuronide was identified as a good surrogate probe for statins when assessing OATP1B1 inhibitory potential using this test system. Inhibition data was used to predict the likelihood of a clinical DDI, using current draft US FDA guidance and recommendations of the International Transporter Consortium. Predictions for AZX indicated the potential for an OATP1B1-mediated DDI in vivo and that a clinical interaction study is warranted to confirm whether AZX is an OATP1B1 inhibitor in the clinic.

MeSH terms

  • Cell Line
  • Drug Interactions
  • Estradiol / pharmacology
  • Estrone / analogs & derivatives
  • Estrone / pharmacology
  • Gemfibrozil / pharmacology
  • Glucuronides / pharmacology
  • HEK293 Cells
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Kinetics
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters / antagonists & inhibitors
  • Organic Anion Transporters / metabolism*
  • Permeability
  • Rifamycins / pharmacology


  • Glucuronides
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • Rifamycins
  • SLCO1B1 protein, human
  • Estrone
  • Estradiol
  • Gemfibrozil
  • estrone sulfate