Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1

Xenobiotica. 2010 Mar;40(3):163-76. doi: 10.3109/00498250903509375.


The effects of human immunodeficiency virus (HIV) protease inhibitors (PI) on the accumulation of the fluorescent bile salt analogue cholyl-glycylamido-fluorescein (CGamF) were determined in organic anion transporting polypeptide (OATP)-1B1 and -1B3-expressing Chinese hamster ovary (CHO) cells. In addition, interaction studies in Caco-2 monolayers, known only to express the OATP2B1 isoform, were conducted using the established OATP substrate estrone 3-sulfate (E3S), since no CGamF accumulation was observed in Caco-2 monolayers. CGamF appeared an excellent substrate for the OATP1B subfamily, with net accumulation clearance values of 7.8 and 142 microl min(-1) mg(-1) protein in OATP1B1 and OATP1B3-transfected cells, respectively. K(i)-values reflecting inhibition of CGamF accumulation by HIV PI correlated well between OATP1B1 and OATP1B3-expressing cells. Lopinavir was the most potent inhibitor (K(i) = 0.5-1.4 microM) of OATP1B-mediated CGamF accumulation compared with atazanavir, darunavir, ritonavir, and saquinavir (K(i) between 1.4 and 3.3 microM). Inhibitory profiles towards OATP2B1-mediated E3S accumulation were different with only indinavir, saquinavir, and ritonavir showing substantial effects. In conclusion, OATP1B3 appears to be a major transport mechanism mediating sodium-independent CGamF accumulation in human liver, and CGamF could be used as a probe substrate for in vitro drug interaction studies. The remarkably potent inhibition of OATP1B1 by lopinavir may explain some clinically relevant drug interactions between lopinavir and OATP1B substrates such as fexofenadine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Caco-2 Cells
  • Cricetinae
  • Cricetulus
  • Estrone / analogs & derivatives
  • Estrone / metabolism
  • Fluoresceins / metabolism
  • HIV Protease Inhibitors / metabolism*
  • HIV Protease Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Kinetics
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters / antagonists & inhibitors
  • Organic Anion Transporters / metabolism*
  • Organic Anion Transporters, Sodium-Independent / antagonists & inhibitors
  • Organic Anion Transporters, Sodium-Independent / metabolism*
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Transfection


  • Fluoresceins
  • HIV Protease Inhibitors
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • SLCO2B1 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • cholylglycylamidofluorescein
  • Estrone
  • estrone sulfate