Darunavir/ritonavir and efavirenz exert differential effects on MRP1 transporter expression and function in healthy volunteers

Background: The efflux transporter MRP1 actively transports antiretroviral and reduces intracellular accumulation In peripheral blood mononuclear cells (PBMCs). We studled MRP1 expression and function In healthy volunteers treated with darunavir/ritonavir and efavirenz. Methods: Seven healthy HIV-negative volunteers were recruited. PBMCs were collected at baseline, 9 days after administration of darunavir (900 mg) and ritonavir (100 mg) once daily, 9 days after coadministration of darunavir/ritonavir and efavirenz (600 mg) once daily and 13 days after administration of efavirenz alone. MRP1 expression was measured in PBMCs using flow cytometry with fluorescein isothiocyanate- conjugated antibody against MRP1 m6. MRP1 expression was also measured in CD4⁺ T-cells with a phycoerythrin-conjugated antibody against CD4. MRP1 efflux function was assessed by incubating PBMCs with carboxyfluorescein diacetate (CFDA) and comparing CFDA fluorescence with and without the modulators MK571 and probenecid. Results: MRP1 expression was reduced after darunavir/ ritonavir administration (geometric mean ratio [GMR] 0.58, 95% confidence interval [95% Cl] 0.51-0.65; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 0.74, 95% Cl 0.64-0.84; P=0.001), but not after efavirenz administration alone (GMR 0.82, 95% Cl 0.64-1.06; P=0.10). MRP1 protein expression was 41% higher in CD4⁺ T-cells. MRP1 efflux function was increased after efavirenz administration (GMR 3.13, 95% Cl 2.73-3.59; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 4.35, 95% Cl 3.35-5.68; P<0.001), but not after darunavir/ritonavir administration (GMR 1.06,§ 95% Cl 0.80-1.42; P=0.42). Conclusions: Darunavir/ritonavir and efavirenz treatment exerted differential effects on MRP1 expression and function. These effects could potentially alter antiviral activity, especially in CD4⁺ T-cells.