Journal
AIDS
Volume 16, Issue 13, Pages 1743-1747Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00002030-200209060-00005
Keywords
efflux pump; multidrug resistance; HIV-1 protease inhibitors; MRP-1
Categories
Ask authors/readers for more resources
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 (r(2)=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. (C) 2002 Lippincott Williams Wilkins.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available