title: Gene, ethnic and gender influences predisposition of adverse drug reactions to artesunate among Malaysians.
abstract: BACKGROUND
  Artesunate (AS) and amodiaquine (AQ) are two prodrugs widely used as antimalarial agents and are metabolized by the CYP P450 2A6 (CYP 2A6) and CYP P450 2C8 (CYP 2C8) enzymes, respectively.
  
  
  OBJECTIVE
  In this study, we aim to investigate the association of both genes on AS and AQ's tolerabilities in the hope of identifying a pharmacogenetic approach that could be useful in prediction and prevention of adverse drug reactions (ADRs) among Malaysian population.
  
  
  METHODS
  In this randomized crossover study, loose and AS/AQ formulations were administered to normal healthy volunteers (n = 24) over two study phases. The drugs' tolerabilities (incidence of facial flushing, giddiness, headache, nausea, abdominal discomfort, progression of liver enzymes and neutrophil counts) were compared between the two treatment arms. Volunteers were also genotyped for the CYP2C8 and CYP2A6 variants.
  
  
  RESULTS
  The frequency of the CYP2A6*1B, CYP2A6*4, CYP2A6*8 and CYP2A6*9 alleles were 54.2%, 16.7%, 4.2% and 10.4%, respectively. No mutations for CYP2C8 gene were, however, detected. Most (96%) of the subjects were of the Malay ethnicity. Subjects having the CYP2A6*1B variants responsible for ultra rapid metabolism of AS suffered a significantly higher incidence of ADRs.
  
  
  CONCLUSIONS
  Our study is the first to report that CYP2A6 genotyping influences AS's ADR. Gender also plays a role where females reported more incidences of nausea (p < 0.05).
  
  
  CONCLUSIONS
  It is concluded that genetic polymorphisms of CYP2A6 as well as gender influence the side effect profiles of subjects receiving AS among this Malaysian population.
authors: Department of Pharmacology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.
authors: Wardah
authors: W
authors: Yusof
authors: Gan Siew
authors: GS
authors: Hua
mesh_terms: D000328:Adult; D000655:Amodiaquine / Q000009:adverse effects* / Q000378:metabolism; D000962:Antimalarials / Q000009:adverse effects* / Q000378:metabolism; D037621:Artemisinins / Q000009:adverse effects* / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics*; D018592:Cross-Over Studies; D065637:Cytochrome P-450 CYP2A6; D065727:Cytochrome P-450 CYP2C8; D004338:Drug Combinations; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008296:Malaysia / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010641:Phenotype; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D055815:Young Adult
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; C515299:amodiaquine, artesunate drug combination; D000655:Amodiaquine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C450259:CYP2C8 protein, human; D065637:Cytochrome P-450 CYP2A6; D065727:Cytochrome P-450 CYP2C8