Interaction of eight HIV protease inhibitors with the canalicular efflux transporter ABCC2 (MRP2) in sandwich-cultured rat and human hepatocytes

Biopharm Drug Dispos. 2010 Mar;31(2-3):178-88. doi: 10.1002/bdd.701.


Hepatotoxicity has been reported as a side-effect in some patients on HIV protease inhibitors (PI). Since transporter interaction has been implicated as a mechanism underlying drug-mediated hepatotoxicity and drug-drug interactions, the interaction of PI with the hepatic canalicular efflux transporter ABCC2 (MRP2; multidrug resistance associated protein-2) was studied. Interaction with ABCC2/Abcc2 was evaluated in human and rat sandwich-cultured hepatocytes using 5(6)-carboxy-2',7'-dichlorofluorescein (CDF) as substrate. In rat hepatocytes, interaction with estradiol-17-beta-D-glucuronide (E17G) efflux was also studied. In human hepatocytes, saquinavir, ritonavir and atazanavir were the most efficient inhibitors of ABCC2-mediated biliary excretion of CDF, whereas in rat hepatocytes indinavir, lopinavir and nelfinavir were the most efficient. No species-similarity was found for ABCC2/Abcc2 inhibition. In rat hepatocytes, the effects on Abcc2 were substrate-dependent as inhibition of biliary excretion of E17G was most pronounced for saquinavir (completely blocked), amprenavir (82% inhibition) and indinavir (68% inhibition). In conclusion, several HIV PI showed substantial ABCC2 inhibition, which, combined with the effects of PI on other hepatobiliary disposition mechanisms, will determine the clinical relevance of these in vitro interaction data.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Anti-HIV Agents / pharmacokinetics*
  • Biological Transport
  • Carbamates / pharmacokinetics
  • Cells, Cultured
  • Fluoresceins / pharmacokinetics
  • Furans
  • HIV Protease Inhibitors / pharmacokinetics*
  • Hepatocytes / metabolism*
  • Humans
  • Indinavir / pharmacokinetics
  • Liver / pathology*
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Nelfinavir / pharmacokinetics
  • Rats
  • Rats, Wistar
  • Ritonavir / pharmacokinetics
  • Saquinavir / pharmacokinetics
  • Sulfonamides / pharmacokinetics


  • ABCC2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-HIV Agents
  • Carbamates
  • Fluoresceins
  • Furans
  • HIV Protease Inhibitors
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • Sulfonamides
  • 2',7'-dichlorofluorescein
  • amprenavir
  • Indinavir
  • Nelfinavir
  • Saquinavir
  • Ritonavir