JAC Advance Access originally published online on May 17, 2007
Journal of Antimicrobial Chemotherapy 2007 60(1):61-67; doi:10.1093/jac/dkm135
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Interindividual variability in the effect of atazanavir and saquinavir on the expression of lymphocyte P-glycoprotein
1 Department of Biopharmaceutical Sciences, University of California San Francisco, 1550 4th Street, San Francisco, CA 94158, USA 2 Pacific Horizon Medical Group, 2351 Clay Street, San Francisco, CA 94115, USA 3 Institute for Human Genetics, University of California San Francisco, 1550 4th Street, San Francisco, CA 94158, USA
Received 12 December 2006; returned 22 February 2007; revised 27 March 2007; accepted 11 April 2007
* Correspondence address. Department of Biopharmaceutical Sciences, 1550 4th Street, Rm RH584E, Box 2911, San Francisco, CA 94143-2911, USA. Tel: +1-415-476-1159; Fax: +1-415-514-4361; E-mail: deanna.kroetz{at}ucsf.edu
Objectives: 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 µM 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.
Keywords: antivirals , protease inhibitors , ABCB1