title: In vitro activities of piperaquine, lumefantrine, and dihydroartemisinin in Kenyan Plasmodium falciparum isolates and polymorphisms in pfcrt and pfmdr1.
abstract: We have analyzed the in vitro chemosensitivity profiles of 115 Kenyan isolates for chloroquine (CQ), piperaquine, lumefantrine (LM), and dihydroartemisinin in association with polymorphisms in pfcrt at codon 76 and pfmdr1 at codon 86, as well as with variations of the copy number of pfmdr1. The median drug concentrations that inhibit 50% of parasite growth (IC(50)s) were 41 nM (interquartile range [IQR], 18 to 73 nM), 50 nM (IQR, 29 to 96 nM), 32 nM (IQR, 17 to 46 nM), and 2 nM (IQR, 1 to 3 nM) for CQ, LM, piperaquine, and dihydroartemisinin, respectively. The activity of CQ correlated inversely with that of LM (r(2) = -0.26; P = 0.02). Interestingly, parasites for which LM IC(50)s were higher were wild type for pfcrt-76 and pfmdr1-86. All isolates had one pfmdr1 copy. Thus, the decrease in LM activity is associated with the selection of wild-type pfcrt-76 and pfmdr1-86 parasites, a feature that accounts for the inverse relationship between CQ and LM. Therefore, the use of LM-artemether is likely to lead to the selection of more CQ-susceptible parasites.
authors.affiliation: Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, Kilifi, Kenya.
authors.forename: Leah
authors.initials: L
authors.lastname: Mwai
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kiara
authors.forename: Abdi
authors.initials: A
authors.lastname: Abdirahman
authors.forename: Lewa
authors.initials: L
authors.lastname: Pole
authors.forename: Anja
authors.initials: A
authors.lastname: Rippert
authors.forename: Abdi
authors.initials: A
authors.lastname: Diriye
authors.forename: Pete
authors.initials: P
authors.lastname: Bull
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: Steffen
authors.initials: S
authors.lastname: Borrmann
authors.forename: Alexis
authors.initials: A
authors.lastname: Nzila
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D005449:Fluorenes / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000469:parasitology*; D026901:Membrane Transport Proteins / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D011110:Polymorphism, Genetic / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics*; D011804:Quinolines / Q000494:pharmacology; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D000078102:Lumefantrine; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D011804:Quinolines; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum; C039060:artenimol; C034759:piperaquine; D010879:Piperazines