title: Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity.
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.
authors.forename: Sanna R
authors.initials: SR
authors.lastname: Rijpma
authors.forename: Jeroen J M W
authors.initials: JJ
authors.lastname: van den Heuvel
authors.forename: Maarten
authors.initials: M
authors.lastname: van der Velden
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Centre, Nijmegen, Netherlands. Jan.Koenderink@radboudumc.nl.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Koenderink
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D011803:Quinine / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D011803:Quinine; D053626:Atovaquone