Janneh O, Back DJ, Khoo SH; International Conference on AIDS (15th : 2004 : Bangkok, Thailand).
Int Conf AIDS. 2004 Jul 11-16; 15: abstract no. TuPpA2033.
The University of Liverpool, Liverpool, United Kingdom
Background: Viral resistance, lack of adherence and pharmacological factors may contribute to HIV treatment failure. The role of transporter pumps such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and breast cancer resistance protein (BCRP) in resistance to antiretrovirals is attracting some attention. Here, using specific inhibitors to MRP, P-gp and BCRP, we sought to define the importance of these transporters in the intracellular accumulation of saquinavir (SQV) in peripheral blood mononuclear cells (PBMCs) from 7 buffy coats. Methods: PBMCs (10x106 cells/ml) were incubated with 10muM of [3H]-SQV at 37degreesC for 30 min, in the absence or presence of 1muM XR9576 and 50muM of verapamil, MK571, probenecid, dipyridamole and GF120918. Data were expressed as cellular accumulation ratio (CAR), being the amount of radiolabelled SQV associated with the cell pellets to the amount in a similar volume of buffer after incubation. Statistical significance was evaluated by ANOVA followed by modified t-test, where significance between control and drug-treated means was assumed if P<0.05. Results: A marked interindividual variability in the accumulation of SQV was observed among the 7 subjects. XR9576 (specific P-gp inhibitor) significantly increased the CAR of SQV in 3/6 subjects (P<0.05), whilst verapamil (P-gp inhibitor) only significantly increased it in 1/6 (P<0.05). Interestingly, 5/7 subjects had their CAR of SQV significantly increased (P<0.05) by MK571 (MRP1 inhibitor). Probenecid (MRP1/2 inhibitor) significantly increased it in 2/6 (P<0.05), with GF120918 (P-gp and BCRP inhibitor) causing a significant increase (P<0.05) in 1/3. Dipyridamole (a nucleoside transport, P-gp and MRP1 inhibitor) caused a significant increase (P<0.05) in 2/2 subjects. Conclusions: The inhibitors had variable effects, suggesting variable differences in the contribution of efflux transporters to intracellular SQV accumulation. Targeted inhibition of drug efflux transporter is a realistic possibility, but may have to be accompanied by screening for these transporters.
Publication Types:
Keywords:
- ABCG2 protein, human
- ATP-Binding Cassette Transporters
- Acridines
- Biological Transport
- GF 120918
- HIV Infections
- Multidrug Resistance-Associated Proteins
- Probenecid
- Quinolines
- Saquinavir
- Tetrahydroisoquinolines
- antagonists & inhibitors
- enzymology
- tariquidar
Other ID:
UI: 102283395
From Meeting Abstracts