Darunavir/ritonavir and efavirenz exert differential effects on MRP1 transporter expression and function in healthy volunteers.
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.
Lee
Lawrence S
LS
National Healthcare Group, Singapore, Singapore. mdcllsu@nus.edu.sg
Soon
Gaik H
GH
Shen
Ping
P
Yong
Eu-Leong
EL
Flexner
Charles
C
Pham
Paul
P
D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology; D048588:Benzoxazines / Q000008:administration & dosage / Q000494:pharmacology; D003521:Cyclopropanes; D000069454:Darunavir; D004359:Drug Therapy, Combination; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018023:HIV Seronegativity / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects* / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome; D055815:Young Adult
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D000069454:Darunavir; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018894:Reverse Transcriptase Inhibitors; D019438:Ritonavir; D013449:Sulfonamides; C098320:efavirenz; C421109:multidrug resistance-associated protein 1