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Malaria Journal
Published in: Malaria Journal 1/2014

Open Access 01-12-2014 | Research

Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity

Authors: Sanna R Rijpma, Jeroen JMW van den Heuvel, Maarten van der Velden, Robert W Sauerwein, Frans GM Russel, Jan B Koenderink

Published in: Malaria Journal | Issue 1/2014

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Abstract

Background

Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceuticals. In this study, a panel of well-established anti-malarial drugs which may affect drug plasma concentrations was tested for interactions with human ABC transport proteins.

Methods

The interaction of chloroquine, quinine, artemisinin, mefloquine, lumefantrine, atovaquone, dihydroartemisinin and proguanil, with transport activity of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP) and multidrug resistance-associated proteins (MRP) 1–4 were analysed. The effect of the anti-malarials on the ATP-dependent uptake of radio-labelled substrates was measured in membrane vesicles isolated from HEK293 cells overexpressing the ABC transport proteins.

Results

A strong and previously undescribed inhibition of BCRP-mediated transport by atovaquone with a 50% inhibitory concentration (IC50) of 0.23 μM (95% CI 0.17-0.29 μM) and inhibition of P-gp-mediated transport by quinine with an IC50 of 6.8 μM (95% CI 5.9-7.8 μM) was observed. Furthermore, chloroquine and mefloquine were found to significantly inhibit P-gp-mediated transport. BCRP transport activity was significantly inhibited by all anti-malarials tested, whereas BSEP-mediated transport was not inhibited by any of the compounds. Both MRP1- and MRP3-mediated transport were significantly inhibited by mefloquine.

Conclusions

Atovaquone and quinine significantly inhibit BCRP- and P-gp- mediated transport at concentrations within the clinically relevant prophylactic and therapeutic range. Co-administration of these established anti-malarials with drugs that are BCRP or P-gp substrates may potentially lead to drug-drug interactions.
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Metadata
Title
Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity
Authors
Sanna R Rijpma
Jeroen JMW van den Heuvel
Maarten van der Velden
Robert W Sauerwein
Frans GM Russel
Jan B Koenderink
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Malaria Journal / Issue 1/2014
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/1475-2875-13-359

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