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JAC Advance Access originally published online on August 13, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 354-358
© 2003 The British Society for Antimicrobial Chemotherapy

Effect of protease inhibitor-containing regimens on lymphocyte multidrug resistance transporter expression

J. Ford1,*, E. R. Meaden1, P. G. Hoggard1, M. Dalton1, P. Newton2, I. Williams2, S. H. Khoo1 and D. J. Back1

1 Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Block H, First Floor, Liverpool L69 3GF; 2 Department of Sexually Transmitted Diseases, Royal Free and University College Medical School,University College London, The Mortimer Market Centre, London WC1E 6AU, UK

Received 16 April 2003; returned 28 May 2003; revised 6 June 2003; accepted 17 June 2003

Background: Increased expression of multidrug resistance transporters, such as P-glycoprotein (P-gp), has been suggested as a potential mechanism for decreased protease inhibitor (PI) availability at certain intracellular sites and tissue compartments.

Objectives: To investigate the effect of PIs on the surface lymphocyte expression of P-gp in vitro and in vivo.

Patients and methods: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy subjects (n = 15) and incubated (72 h) with 10 µM of each PI studied (saquinavir, ritonavir, nelfinavir, indinavir, amprenavir and lopinavir), or dimethyl sulphoxide (DMSO) control. PBMCs were also isolated from HIV-infected subjects (n = 50; viral load <50 copies/mL) on a PI- or a non-PI-containing combination antiretroviral regimen. P-gp expression was analysed by flow cytometry.

Results: No differences in surface P-gp expression on lymphocytes, CD4+ or CD8+ lymphocyte subsets were observed following incubation with 10 µM saquinavir, ritonavir, indinavir, amprenavir or lopinavir in vitro. Nelfinavir, however, increased P-gp expression. In vivo, no difference in P-gp expression on total lymphocytes was observed between patients receiving a PI-containing regimen [saquinavir n = 9, ritonavir n = 6, nelfinavir n = 7, indinavir n = 7 and lopinavir/ritonavir n = 13, and two nucleoside reverse transcriptase inhibitors (NRTIs)] and patients receiving a control regimen of three NRTIs alone (n = 8).

Conclusion: This study suggests that, of the PIs, only nelfinavir increases P-gp expression in vitro, and in vivo the PI class of antiretrovirals do not increase P-gp expression on lymphocytes. It is clear that factors other than PI induction are important in the inter-individual variability in the lymphocyte expression of P-gp.

Keywords: P-glycoprotein, flow cytometry, HIV, CD4+, CD8+, HAART, multidrug resistance transporters.

* Corresponding author. Tel: +44-151-794-5565; Fax: +44-151-794-5656; E-mail: jford{at}liv.ac.uk


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