The protease inhibitor ritonavir inhibits the functional activity of the multidrug resistance related-protein 1 (MRP-1).
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.
Olson
Douglas P
DP
AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Scadden
David T
DT
D'Aquila
Richard T
RT
De Pasquale
Maria Pia
MP
D019380:Anti-HIV Agents / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000633:toxicity; D005047:Etoposide / Q000378:metabolism / Q000633:toxicity; D005434:Flow Cytometry; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects* / Q000378:metabolism; D011339:Probenecid / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D019380:Anti-HIV Agents; D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D017320:HIV Protease Inhibitors; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011339:Probenecid; D018894:Reverse Transcriptase Inhibitors; D019438:Ritonavir