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

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.

Biologically active quinoline and quinazoline alkaloids part II

“…Recently, increasing numbers of papers have focused on the mechanism of antimalarial drugs. Studies in 2014 showed that quinine significantly inhibited breast cancer resistance protein (BCRP) mediated and P‐gp‐mediated transport at concentrations within the clinically relevant prophylactic and therapeutic range, and inhibited adenosine triphosphate (ATP) binding cassette transporter activity . Quinidine and cinchonine, which have identical stereochemistry at carbons 8 and 9, exhibited stronger inhibition of human and Drosophila melanogaster serotonin receptor transporter (hSERT and dSERT) function than their enantiomers, quinine, and cinchonidine .…”

Expression of Organic Anion Transporting Polypeptide 1A2 in Red Blood Cells and Its Potential Impact on Antimalarial Therapy

“…For a wide variety of drugs, including several antimalarial compounds, drug transporters of the ATP-binding cassette (ABC), solute carrier (SLC), or solute carrier organic anion (SLCO) family are involved in transmembrane transfer (Konig et al, 2013). For example, mefloquine, quinine, and chloroquine are inhibitors or substrates of efflux pumps such as P-glycoprotein (P-gp/ABCB1) (Riffkin et al, 1996;Pham et al, 2000;Rijpma et al, 2014), multidrug-resistance protein 1 (MRP1, ABCC1) and multidrug-resistance protein 4 (MRP4, ABCC4) (Wu et al, 2005), and chloroquine and quinine have been identified as inhibitors and substrates of multidrug and toxin extrusion protein 1 (MATE1, SLC47A1) and organic cation transporters (OCTs) (Muller et al, 2011;Nies et al, 2012). In addition, there is evidence that quinine interacts with organic anion transporting polypeptides (OATPs), in particular OATP1A2, which has been shown to transport N-methyl-quinine (Kullak-Ublick et al, 2001;Shitara et al, 2002).…”

Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection

“…Quinine concentrations were below the therapeutic range in 50% of the patients, however all were successfully treated for malaria. [20] As quinine is an inhibitor of P-gp,[21] an interaction with maraviroc, a P-gp substrate, cannot be excluded. Cobicistat would be expected to increase exposure to quinine via CYP3A4 inhibition.…”