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In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine

Owen, A., Janneh, O., Hartkoorn, R. C., Chandler, B., Bray, Patrick, Martin, P., Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192, Hart, C. Anthony, Khoo, S. H. and Back, D. J. (2005) 'In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine'. Journal of Pharmacology and Experimental Therapeutics, Vol 314, Issue 3, pp. 1202-1209.

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Abstract

Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) 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 four other protease inhibitors (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 that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration 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 vivo.

Item Type: Article
Uncontrolled Keywords: multidrug-resistance protein-1 immunodeficiency-virus type-1 p-glycoprotein expression hiv protease inhibitors intracellular accumulation cell-lines chloroquine transport mrp1 individuals
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 268.5 Antiviral agents (General)
WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503.2 Therapy
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1124/jpet..105.086272
Depositing User: Ms Julia Martin
Date Deposited: 21 Sep 2011 14:06
Last Modified: 06 Feb 2018 13:03
URI: http://archive.lstmed.ac.uk/id/eprint/1924

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