title: PFMDR1 POLYMORPHISMS INFLUENCE ON IN VITRO SENSITIVITY OF THAI PLASMODIUM FALCIPARUM ISOLATES TO PRIMAQUINE, SITAMAQUINE AND TAFENOQUINE.
abstract: Primaquine (PQ), an 8-aminoquinoline, is considered a tissue schizonticide drug for radical cure in vivax and ovale malaria, with minimal impact on asexual erythrocytic stages at therapeutic concentrations. Tafenoquine (TQ), a new 8-aminoquinoline analog of PQ, is active against both malaria parasite tissue and blood stages and is being promoted as a drug candidate for antimalarial chemotherapy and chemoprophylaxis and potential transmission blocking against Plasmodium vivax and P. falciparum. This study compared in vitro sensitivity of Thai P. falciparum isolates against three 8-aminoquinolines, PQ, TQ and sitamaquine (SQ), a related 8-aminoquinoline and assessed the importance of pfmdr1 polymorphism on the in vitro response. Seventy-eight laboratory adapted Thai P. falciparum isolates were evaluated for in vitro sensitivity to the three 8-aminoquinolines using a radioisotopic assay, and pfmdr1 polymorphisms were determined using PCR-based methods. All three drugs have weak antiplasmodial activity against asexual erythrocytic stage with SQ being the most potent by almost 10 folds. Cross susceptibility was observed in all three 8-aminoquinolines. Parasites containing pfmdr1 86Y, 184Y or 1034S allele exhibit significantly higher PQ IC₅₀. TQ sensitivity was reduced in those parasites containing pfmdr1 86Y, 1034S or 1042N allele. However, there was no significant influence of pfmdr1 alleles on SQ sensitivity. The data highlight unique differences among three representative 8-aminoquinoline drugs that may be useful in understanding their potential utility in antimalarial development.
authors.forename: Napaporn
authors.initials: N
authors.lastname: Kaewpruk
authors.forename: Peerapan
authors.initials: P
authors.lastname: Tan-ariya
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.forename: Naruemon
authors.initials: N
authors.lastname: Sitthichot
authors.forename: Nantana
authors.initials: N
authors.lastname: Suwandittakul
authors.forename: Mathirut
authors.initials: M
authors.lastname: Mungthin
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics; D011319:Primaquine / Q000494:pharmacology*; D013785:Thailand
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011319:Primaquine; C513498:Mdr1 protein, Plasmodium falciparum; C055852:tafenoquine; C080436:8-aminoquinoline