JAC Advance Access published online on August 13, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg381
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Department of Pharmacology
and Therapeutics, University of Liverpool, 70 Pembroke Place, Block
H,
First Floor, Liverpool L69 3GF;
* Corresponding author. E-mail: jford{at}liv.ac.uk.
Received 16 April 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.
Effect of protease inhibitor-containing regimens
on lymphocyte multidrug resistance transporter expression
2 Department
of Sexually Transmitted Diseases, Royal Free and University College Medical
School,University College London, The Mortimer Market Centre, London
WC1E 6AU, UK
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