Interindividual variability in the effect of atazanavir and saquinavir on the expression of lymphocyte P-glycoprotein.
OBJECTIVE
ABCB1 encodes the efflux transporter P-glycoprotein (P-gp), which regulates the intracellular concentration of many xenobiotics, including several HIV protease inhibitors (PIs). Exposure to some xenobiotics, such as the antibiotic rifampicin, increases P-gp expression. In the present study, we investigated the effect of the HIV PIs saquinavir and atazanavir on the expression and function of ABCB1 and P-gp in primary and cultured lymphocytes, as well as the molecular interactions between these drugs and P-gp. ABCB1 and P-gp expression and function were examined in lymphocyte samples from healthy subjects before and after atazanavir-boosted saquinavir treatment. Expression and function were also studied in CEM cells following exposure to atazanavir and saquinavir. The inhibitory effects of these drugs were investigated in ABCB1-transfected HEK293T cells.


METHODS
P-gp expression and function were measured by flow cytometry. ABCB1 mRNA expression was evaluated using quantitative RT-PCR.


RESULTS
There were no overall changes in ABCB1 or P-gp expression or function after saquinavir-atazanavir treatment in primary lymphocyte samples. However, there was considerable interindividual variability in baseline lymphocyte ABCB1 expression, as well as in the degree of change in ABCB1 expression after saquinavir-atazanavir administration. In cell culture, 5 microM saquinavir increased ABCB1 levels, although it did not affect P-gp expression. Atazanavir inhibited P-gp function at concentrations above therapeutic levels.


CONCLUSIONS
Differences in lymphocyte ABCB1 expression, which may be caused by genetic polymorphisms in ABCB1 or its regulatory partners, are a likely cause of interindividual variation in the disposition and efficacy of clinically relevant P-gp substrates, including HIV PIs.
Chinn
Leslie W
LW
Department of Biopharmaceutical Sciences, University of California San Francisco, 1550 4th Street, San Francisco, CA 94158, USA.
Gow
Jason M
JM
Tse
Man Ming
MM
Becker
Stephen L
SL
Kroetz
Deanna L
DL
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000069446:Atazanavir Sulfate; D002460:Cell Line; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D019258:Saquinavir / Q000494:pharmacology*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019258:Saquinavir