Human immunodeficiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines expressing these transporters

The human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs)-s aquinavir, ritonavir, nelfinavir, and indinavir-interact with the ABC-type multidrug transporter proteins MDR1 and MRP1 in CEM T-lymphocytic cell line s. Calcein fluorescence was significantly enhanced in MDR1(+) CEM/VBL100 an d MRP1(+) CEM/VM-15 cells incubated in the presence of various HIV PIs and calcein acetoxymethyl ester, HIV PIs also enhanced the cytotoxic activity o f doxorubicin, a known substrate for MDR1 and MRP1, in both VBL100 and VM-1 -5 CEM lines. Saquinavir, ritonavir, and nelfinavir enhanced doxorubicin to xicity in CEM/VBL100 cells by approximately three- to sevenfold. Saquinavir and ritonavir also enhanced doxorubicin toxicity in CEM/VM-1-5 cells. HIV- 1 replication was effectively inhibited by the various PIs in all of the ce ll lines, and the 90% inhibitory concentration for a given compound was com parable between the different cell types. Therefore, overexpression of MDR1 or MRP1 by T lymphocytes is not likely to limit the antiviral efficacy of HIV PI therapy.