Inhibition of P-glycoprotein and multidrug resistance-associated proteins modulates the intracellular concentration of lopinavir in cultured CD4 T cells and primary human lymphocytes.

摘要: Background: HIV protease inhibitors (HPIs) are an important component of highly active antiretroviral therapy. However, the activity drug efflux transporters, such as P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRP1/MRP2), may limit intracellular accumulation. Drugs that inhibit may, in combination with HPIs, enhance clinical efficacy drugs. Methods: The transport [ 14 C]Iopinavir was evaluated peripheral blood mononuclear cells (PBMCs) absence or presence known inhibitors: tariquidar (P-gp), MK571 (MRP), frusemide (MRP1/2), dipyridamole (MRP1/P-gp) probenecid (MRP2/OATP). effects ritonavir, amprenavir atazanavir on accumulation lopinavir were also cultured CD4 + T-lymphoblastoid [CEM (parental), CEM VBL (P-gp-overexpressing) E1000 (MRPI-overexpressing)] PBMCs. relative expression PBMCs assessed by flow cytometric real-time PCR methods. Results: Tariquidar, MK571, all significantly increased PBMCs, whereas decreased it. cellular ratio (CAR) a concentration-dependent manner both cell types. P-gp, MRP1 MRP2 mRNA variable individually did not correlate CARs lopinavir. Conclusions: We provide evidence is substrate MRP2. concentration when co-incubated Manipulation transporters be useful strategy for increasing thereby enhancing