The protease inhibitor ritonavir inhibits the functional activity of the multidrug resistance related-protein 1 (MRP-1)

AIDS. 2002 Sep 6;16(13):1743-7. doi: 10.1097/00002030-200209060-00005.


Background: Efflux pumps situated on the plasma membrane, such as P-glycoprotein (Pgp) and the multidrug resistance related-protein 1 (MRP-1), have been shown to extrude HIV protease inhibitors from the cell. MRP-1 is present on many barrier sites throughout the body, such as the blood-brain and blood-testis interfaces and could reduce the concentration of protease inhibitors in these sanctuary sites for HIV-1 replication. Factors that modulate efflux pump function in vivo are poorly defined.

Objective: To analyze the inhibitory potential of the anti-retroviral drugs indinavir, amprenavir, ritonavir, lamivudine or zidovudine to modulate MRP-1 function.

Methods: Effect of anti-HIV drugs on the efflux pump activity of MRP-1 was evaluated in the presence of increasing concentrations of human plasma, using UMCC-1/VP cells which stably over-express MRP-1. MRP-1 activity was abrogated by probenecid. The potential of blocking MRP-1 function for an extended (3 day) time period, was also examined in MRP-1 over-expressing cells cultured with either probenecid or the anti-retroviral drugs and a cytotoxic compound (etoposide) that is transported by MRP-1.

Results: Ritonavir inhibited the functional activity of MRP-1 similarly to probenecid, as demonstrated by re-sensitization of MRP-1 over-expressing cells to cytotoxic effects of etoposide. Inhibition by ritonavir was inversely related to the concentration of human plasma added to the cells (r2 = 0.89). Other anti-HIV drugs didn't affect the MRP-1 mediated efflux of etoposide.

Conclusions: These data may be exploitable to further improve sanctuary site concentrations of anti-HIV or anti-cancer drugs by using ritonavir as a lead compound to develop more potent MRP-1 inhibitors.

MeSH terms

  • Anti-HIV Agents / metabolism
  • Antineoplastic Agents, Phytogenic / metabolism
  • Antineoplastic Agents, Phytogenic / toxicity
  • Etoposide / metabolism
  • Etoposide / toxicity
  • Flow Cytometry
  • HIV Protease Inhibitors / pharmacology*
  • Humans
  • Multidrug Resistance-Associated Proteins / drug effects*
  • Multidrug Resistance-Associated Proteins / metabolism
  • Probenecid / metabolism
  • Reverse Transcriptase Inhibitors / metabolism
  • Ritonavir / pharmacology*
  • Tumor Cells, Cultured


  • Anti-HIV Agents
  • Antineoplastic Agents, Phytogenic
  • HIV Protease Inhibitors
  • Multidrug Resistance-Associated Proteins
  • Reverse Transcriptase Inhibitors
  • Etoposide
  • Ritonavir
  • Probenecid