title: PfCRT and PfMDR1 modulate interactions of artemisinin derivatives and ion channel blockers.
abstract: Treatment of the symptomatic asexual stage of Plasmodium falciparum relies almost exclusively on artemisinin (ART) combination therapies (ACTs) in endemic regions. ACTs combine ART or its derivative with a long-acting partner drug to maximize efficacy during the typical three-day regimen. Both laboratory and clinical studies have previously demonstrated that the common drug resistance determinants P. falciparum chloroquine resistance transporter (PfCRT) and multidrug resistance transporter (PfMDR1) can modulate the susceptibility to many current antimalarial drugs and chemical compounds. Here we investigated the parasite responses to dihydroartemisinin (DHA) and various Ca(2+) and Na(+) channel blockers and showed positively correlated responses between DHA and several channel blockers, suggesting potential shared transport pathways or mode of action. Additionally, we demonstrated that PfCRT and PfMDR1 could also significantly modulate the pharmacodynamic interactions of the compounds and that the interactions were influenced by the parasite genetic backgrounds. These results provide important information for better understanding of drug resistance and for assessing the overall impact of drug resistance markers on parasite response to ACTs.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.|Division of Preclinical Development, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Eastman
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Pwint
authors.initials: P
authors.lastname: Khine
authors.affiliation: Division of Preclinical Development, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.affiliation: Division of Preclinical Development, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Xin-Zhuan
authors.initials: XZ
authors.lastname: Su
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D002121:Calcium Channel Blockers; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D008012:Lidocaine / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism*; D026941:Sodium Channel Blockers
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D002121:Calcium Channel Blockers; D002738:Chloroquine; D008012:Lidocaine; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D026941:Sodium Channel Blockers; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum; C039060:artenimol