title: Full-gene sequencing analysis of NAT2 and its relationship with isoniazid pharmacokinetics in Venezuelan children with tuberculosis.
abstract: BACKGROUND
  Genetic variants in NAT2 are associated with pharmacokinetic variation of isoniazid, the cornerstone of antituberculosis treatment. We investigated the acetylator genotype and phenotype in children on antituberculosis treatment that were previously shown to have low plasma isoniazid levels.
  
  
  METHODS
  NAT2 genotyping and phenotyping, represented as metabolic ratio of acetylisoniazid over isoniazid and as isoniazid half-life, were performed in 30 Venezuelan children.
  
  
  RESULTS
  Most children carried genotypes resulting in an intermediate or low enzyme activity (43 and 40%, respectively). Isoniazid exposure differed between genotypically slow and rapid acetylators (13.3 vs 4.5 h×mg/l, p < 0.01). Both the metabolic ratio as well as the half-life of isoniazid distinguished genotypically slow from genotypically rapid or intermediate acetylators (all p ≤ 0.01).
  
  
  CONCLUSIONS
  In Venezuelan children a clear difference in isoniazid pharmacokinetics and acetylator phenotype between genotypically slow and genotypically intermediate or rapid acetylating children was observed. Original submitted 31 July 2013; Revision submitted 11 November 2013.
authors.affiliation: Laboratorio de Tuberculosis, Instituto de Biomedicina, Universidad Central de Venezuela, Caracas, Venezuela.
authors.forename: Lilly M
authors.initials: LM
authors.lastname: Verhagen
authors.forename: Marieke Jh
authors.initials: MJ
authors.lastname: Coenen
authors.forename: Diana
authors.initials: D
authors.lastname: López
authors.forename: Juan F
authors.initials: JF
authors.lastname: García
authors.forename: Jacobus H
authors.initials: JH
authors.lastname: de Waard
authors.forename: Mascha M V A P
authors.initials: MM
authors.lastname: Schijvenaars
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Hermans
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
mesh_terms: D000293:Adolescent; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007538:Isoniazid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014376:Tuberculosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014687:Venezuela
chemical_list: D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; C510884:acetylisoniazid; D007538:Isoniazid