title: In vitro synergy and enhanced murine brain penetration of saquinavir coadministered with mefloquine.
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.
authors.affiliation: Department of Pharmacology and Therapeutics, The University of Liverpool, UK. aowen@liv.ac.uk
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: Omar
authors.initials: O
authors.lastname: Janneh
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Hartkoorn
authors.forename: Becky
authors.initials: B
authors.lastname: Chandler
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Bray
authors.forename: Phillip
authors.initials: P
authors.lastname: Martin
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Hart
authors.forename: Saye H
authors.initials: SH
authors.lastname: Khoo
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000962:Antimalarials; D001921:Brain / Q000378:metabolism*; D004357:Drug Synergism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D015767:Mefloquine / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000235:genetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D019258:Saquinavir / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D017320:HIV Protease Inhibitors; D015767:Mefloquine; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D019258:Saquinavir; C421109:multidrug resistance-associated protein 1