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JAC Advance Access originally published online on September 11, 2009
Journal of Antimicrobial Chemotherapy 2009 64(5):1002-1007; doi:10.1093/jac/dkp335
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Intracellular accumulation of efavirenz and nevirapine is independent of P-glycoprotein activity in cultured CD4 T cells and primary human lymphocytes

Omar Janneh1,2,*, Becky Chandler2, Ruben Hartkoorn2, Wai San Kwan2, Claire Jenkinson2, Sorcha Evans2, David J. Back2, Andrew Owen2 and Saye H. Khoo2

1 Department of Biomolecular and Sports Sciences, Coventry University, Coventry CV1 5FB, UK 2 Pharmacology Research Laboratories, First Floor, Block H, 70 Pembroke Place, University of Liverpool, Liverpool L69 3GF, UK

Received 15 June 2009; returned 17 July 2009; revised 7 August 2009; accepted 17 August 2009

* Corresponding author. Tel: +44-(0)2476-888-632; Fax: +44-(0)2476-888-778; E-mail: o.janneh{at}coventry.ac.uk

Background: Interaction of antiretrovirals with drug transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), breast cancer resistance protein (BCRP) and solute carrier organic anion transporter (SLCO) may influence the emergence of viral mutants by altering intracellular drug concentrations. Here we characterize the effect of transporter expression in a variety of cell types such as control CEM, CEMVBL (P-gp-overexpressing), CEME1000 (MRP1-overexpressing), MT4, control MDCKII, MDCKIIMDR1 (P-gp-overexpressing) and peripheral blood mononuclear cells (PBMCs) on the uptake of [14C]efavirenz and [3H]nevirapine. We also investigated the lipophilicity of [14C]efavirenz and [3H]nevirapine.

Methods: The expression of P-gp, MRP1, MRP2, SLCO1A2, 1B1, 1B3, 2B1, 3A1 and 4A1 was assessed by PCR. Inhibitors of P-gp (XR9576, GF120918, dipyridamole) and MRP (MK571, frusemide, dipyridamole), and SLCO substrate or inhibitor (estrone-3-sulphate or montelukast, respectively) were used to study the role of drug transporters in the accumulation of [14C]efavirenz and [3H]nevirapine. Lipophilicity was measured by the octanol/saline partition coefficient.

Results: CEM cells, MT4 cells and PBMCs express various SLCO isoforms, with SLCO3A1 detected in all of the cells. XR9576, dipyridamole and GF120918 had no effects on the accumulation of [14C]efavirenz, while MK571 and frusemide produced variable effects in the cells. The accumulation of [14C]efavirenz was significantly decreased in all the cells by montelukast and estrone-3-sulphate.

Conclusions: P-gp expression had no effect on the accumulation of [14C]efavirenz and [3H]nevirapine. MRP1/2 expression, lipophilicity and SLCO-like transporters (possibly SLCO3A1) may have greater influence on the accumulation of [14C]efavirenz than [3H]nevirapine.

Keywords: transport , MRP , SLCO/OATP


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