P-glycoprotein and MRP1 expression and reduced ritonavir and saquinavir accumulation in HIV-infected individuals

OBJECTIVES: Efflux transporters may play a role in lowering intracellular drug concentrations. As the HIV protease inhibitors are substrates for the efflux transporters P-glycoprotein and MRP, we wished to investigate whether differences in expression of these transporters on human lymphocytes correlated with intracellular concentrations of ritonavir and saquinavir. PATIENTS AND METHODS: Drug efflux transporter expression (P-glycoprotein and MRP1) on peripheral blood mononuclear cells isolated from HIV-positive patients was investigated using flow cytometry. In addition, plasma and intracellular ritonavir and saquinavir concentrations were measured by HPLC/mass spectrometry. The ratio of intracellular:plasma drug concentration was used to quantify intracellular drug accumulation. RESULTS: Patients with lower MRP1 expression (<median) had a significantly higher accumulation of both ritonavir and saquinavir than those with higher MRP1 expression (P = 0.035, CI = -1.70 to -0.06 and P = 0.043, CI = -12.79 to -0.11, respectively). Ritonavir accumulation was significantly greater in patients with lower P-glycoprotein expression (<median) than in patients with higher expression (P = 0.014, CI = -1.56 to -0.14). There was no relationship between saquinavir accumulation in patients and P-glycoprotein expression (P = 0.219, CI = -5.02 to 2.40). Combining expression of P-glycoprotein and MRP1 (expression index, EI = [(P-glycoprotein - 1) + (MRP1 - 1) x 100]) resulted in a statistically significant relationship between transporter expression and intracellular accumulation of both saquinavir (r(2) = 0.195, P = 0.035) and ritonavir (r(2) = 0.220, P = 0.049). CONCLUSION: Increased expression of P-glycoprotein and MRP1 on lymphocytes is associated with lower intracellular accumulation of saquinavir and ritonavir. These two transporters may play a role in the efflux of ritonavir and saquinavir from lymphocytes in vivo.