BACKGROUND: The efflux transporter MRP1 actively transports antiretrovirals and reduces intracellular accumulation in peripheral blood mononuclear cells (PBMCs). We studied 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 MRP1m6. 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% CI] 0.51-0.65; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 0.74, 95% CI 0.64-0.84; P=0.001), but not after efavirenz administration alone (GMR 0.82, 95% CI 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% CI 2.73-3.59; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 4.35, 95% CI 3.35-5.68; P<0.001), but not after darunavir/ritonavir administration (GMR 1.06, 95% CI 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.
BACKGROUND: The efflux transporter MRP1 actively transports antiretrovirals and reduces intracellular accumulation in peripheral blood mononuclear cells (PBMCs). We studied 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 MRP1m6. 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% CI] 0.51-0.65; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 0.74, 95% CI 0.64-0.84; P=0.001), but not after efavirenz administration alone (GMR 0.82, 95% CI 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% CI 2.73-3.59; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 4.35, 95% CI 3.35-5.68; P<0.001), but not after darunavir/ritonavir administration (GMR 1.06, 95% CI 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.
Authors: Paul Shapshak; Pandjassarame Kangueane; Robert K Fujimura; Deborah Commins; Francesco Chiappelli; Elyse Singer; Andrew J Levine; Alireza Minagar; Francis J Novembre; Charurut Somboonwit; Avindra Nath; John T Sinnott Journal: AIDS Date: 2011-01-14 Impact factor: 4.177
Authors: Cecile D Lahiri; Sijia Tao; Yong Jiang; Anandi N Sheth; Edward P Acosta; Vincent C Marconi; Wendy S Armstrong; Raymond F Schinazi; Aswani Vunnava; Sara Sanford; Ighovwerha Ofotokun Journal: AIDS Date: 2015-06-01 Impact factor: 4.177
Authors: Gaik H Soon; Ping Shen; Eu-Leong Yong; Paul Pham; Charles Flexner; Lawrence Lee Journal: Antimicrob Agents Chemother Date: 2010-04-12 Impact factor: 5.191