Abstract
BackgroundTherapeutic 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.MethodsThe 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.ResultsA 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.ConclusionsAtovaquone 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.
Highlights
Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment
Significant inhibition of taurocholic acid transport by bile salt export pump (BSEP) was observed for ATO, which reduced uptake to 54% (p < 0.001) and MQ, which reduced uptake to 72% (p = 0.037)
Induction of BSEP transport activity was found for CQ (117%, p < 0.001), ART (117%, p < 0.001) and DHA (114%, p < 0.001) (Figure 1C)
Summary
Therapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. ATP binding cassette (ABC) transport proteins are 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. The first-line treatment as recommended by the World Health Organization (WHO) currently consists of artemisinin-based combination therapy [2]. Resistance against these regimens has been detected and the number of anti-malarials that can be subsequently applied are limited [3]. Toxic effects by unintended elevated blood plasma concentrations, should be avoided
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