title: The pharmacogenetics of antimalaria artemisinin combination therapy.
abstract: BACKGROUND
  Plasmodium falciparum malaria is one of the world's most lethal infectious diseases, commanding millions of drug administrations per year. The pharmacogenetics of these drugs is poorly known, although its application can be pivotal for the optimized management of this disease.
  
  
  METHODS
  The main components of artemisinin combination therapy (ACT), the worldwide main antimalarial strategy, are metabolized by the polymorphic CYP3A4 (mefloquine, artemether, lumefantrine), CYP2C8 (amodiaquine), CYP2A6 (artesunate) and CYP1A1/2 (amodiaquine/desethylamodiaquine), with dihydroartemisinin being acted by Phase II UDP-glucuronosyltransferases. The worldwide adoption of ACT is leading to a large number of antimalarial treatments. Simultaneously, the feared development of parasite drug resistance might drive dosing increases. In these scenarios of increased drug exposure, pharmacogenetics can be a key tool supporting evidence-based medicine aiming for the longest possible useful lifespan of this important chemotherapy.
  
  
  CONCLUSIONS
  Translation in this moment is not operationally possible at an individual level, but large population studies are achievable for: i) the development of robust pharmacogenetics markers; and ii) the parallel development of a pharmacogenetic cartography of malaria settings. Advances in the understanding of antimalarial pharmacogenetics are urgent in order to protect the exposed populations, enhance the effectiveness of ACT and, consequently, contributing for the long aimed elimination of the disease.
authors: Karolinska Institute, Division of Pharmacogenetics, Department of Physiology and Pharmacology, Stockholm, Sweden.
authors: Rita
authors: R
authors: Piedade
authors: José Pedro
authors: JP
authors: Gil
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry / Q000627:therapeutic use; D000962:Antimalarials / Q000737:chemistry / Q000627:therapeutic use*; D037621:Artemisinins / Q000737:chemistry / Q000627:therapeutic use*; D000077332:Artesunate; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D004351:Drug Resistance; D004983:Ethanolamines / Q000737:chemistry / Q000627:therapeutic use; D019317:Evidence-Based Medicine; D005449:Fluorenes / Q000737:chemistry / Q000627:therapeutic use; D005819:Genetic Markers; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D015767:Mefloquine / Q000737:chemistry / Q000627:therapeutic use; D010597:Pharmacogenetics / Q000379:methods*; D010963:Plasmodium falciparum / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D005819:Genetic Markers; D000077332:Artesunate; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C450259:CYP2C8 protein, human; D065637:Cytochrome P-450 CYP2A6; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000078102:Lumefantrine; D015767:Mefloquine