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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 27, 2005; DOI: 10.1124/jpet.105.086272

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Received for publication March 14, 2005.
Revised May 26, 2005.
Accepted for publication May 26, 2005.

In-vitro synergy and enhanced murine brain penetration of SQV co-administered with mefloquine

Andrew Owen 1*, Omar Janneh 1, Ruben Hartkoorn 1, Becky Chandler 1, Patrick Bray 2, Phillip Martin 1, Stephen A Ward 2, C Anthony Hart 1, Saye H Khoo 1, David J Back 1

1 University of Liverpool 2 Liverpool School of Tropical Medicine

* Address correspondence to: E-mail: aowen{at}liv.ac.uk

Abstract

Highly active antiretroviral therapy has substantially improved prognosis in HIV. However, the integration of proviral DNA, development of viral resistance and lack of permeability of drugs into sanctuary sites (brain, lymphocyte etc) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug, chloroquine (CQ), has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ) and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells. Furthermore, enhancement of the antiviral activity of SQV and 4 other PIs by MQ was observed in MT4 cells, indicating a class specific rather than a drug specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ; and MQ was also shown to displace SQV from orosomucoid (AAG) in vitro. Finally, co-administration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a >3 fold and >2 fold increase in the tissue:blood ratio for brain and testis respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in HIV positive patients.


Key words: Antimalarial, Antiretroviral, Drug transport, HIV, chloroquine, protease inhibitors


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