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 Ͼ3-fold and Ͼ2-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.

MRP (ABCC) Transporters-Mediated Efflux of Anti-HIV Drugs, Saquinavir and Zidovudine, from Human Endothelial Cells

“…These previous observations showed that several HPIs are effluxed from brain ECs predominantly by the MDR-1 transporter. Neither MRP expression nor MRPassociated efflux function was found to be significantly associated with HPI efflux from mouse brain (33). Hence, approaches to suppress the efflux of therapeutic agents from the human brain had been directed towards a specific blockade of the MDR-1, but not via inhibition of the MRP transporters (32,52,53).…”

“…However, the role of different transporters in drug-efflux from the human brain had been derived from indirect evidences, from in vitro cultured brain microvessel ECs from mice (32,33), or rats (50,51). These previous observations showed that several HPIs are effluxed from brain ECs predominantly by the MDR-1 transporter.…”

“…Both MDR-1 and MRPs were shown to limit the brain uptake of saquinavir in mice (32). Enhanced brain penetration of saquinavir was observed in murine CNS following coadministration of mefloquine, an inhibitor of MDR-1 (33). The nucleotide transporters MRP-4 and MRP-5 have also been shown to efflux several of the NRTIs, such as zidovudine (AZT) and didanosine (ddC) (28,34,35).…”

Stronger Activity of Human Immunodeficiency Virus Type 1 Protease Inhibitors against Clinical Isolates of Plasmodium vivax than against Those of P. falciparum

“…HIV PIs and antimalarials, such as mefloquine, are substrates for P glycoprotein (Pgp) efflux pumps; consequently, their pharmacodynamics and pharmacokinetics are modulated by Pgp cellular transport (19,38). Preliminary work on a Pgp in P. falciparum (Pfmdr1) suggests that its amplification is not associated with the synergistic action of PIs with mefloquine (31).…”

Synergistic Interactions of the Antiretroviral Protease Inhibitors Saquinavir and Ritonavir with Chloroquine and Mefloquine against Plasmodium falciparum In Vitro

“…The synergy of mefloquine when used with HIV PIs against HIV has been proposed to be due, at least in part, to the ability of the HIV PIs to inhibit mefloquine efflux (14). It is unknown whether the HIV PIs may be able to alter drug efflux in Plasmodium falciparum, and if they can, whether this will have any ramifications for the treatment of multidrug-resistant parasites.…”