Age-distribution and genotype-phenotype correlation for N-acetyltransferase in Argentine children under isoniazid treatment.
BACKGROUND
Metabolic clearance of isoniazid (INH) may be up to 10 times faster in individuals who are rapid acetylators compared with slow acetylators. In addition, the acetylation phenotype has been suggested to change with age. A better knowledge of the age distribution of the acetylation genotype and phenotype in children requiring INH for tuberculosis treatment or prevention could be important to optimize safety and efficacy of INH use.


OBJECTIVE
The aim of the present study was to evaluate the genotype and phenotype of NAT2 in an Argentinean pediatric population rom Buenos Aires. In addition, we wanted to describe genotype-phenotype correlation, as well as its distribution at different ages.


METHODS
NAT2 genotyping was performed by RFLP technique, searching for common polymorphisms. Acetylisoniazid and isoniazid concentrations were measured by HPLC and NAT2 phenotype was defined from the ratio of both concentrations (Metabolic Ratio, MR).


RESULTS
Almost half of the patients (46.02%) possessed wild-type haplotype, with 17.05% of individuals having two fully functional alleles, 57.95% one fully functional allele and 25% with no fully functional allele. According to phenotype, most children (96.59%) were classified as fast acetylators, whereas 1.14% of the cases were intermediate and 2.27% slow acetylators. There was a positive association between age and MR (R = 0.52985, p < 0.000001) with a significant MR difference between age categories (p < 0.001).


CONCLUSIONS
We found a high proportion of rapid acetylators compared with other populations. Acetylator phenotype showed a positive correlation with age, with a significant change around the 4th year of life.
Guillermo Alberto
GA
Keller
Lucas
L
Fabian
Matías
M
Gomez
Claudio Daniel
CD
Gonzalez
Roberto Alejandro
RA
Diez
Guillermo
G
Di Girolamo
D000293:Adolescent; D017677:Age Distribution; D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D001118:Argentina; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005838:Genotype; D006801:Humans; D007223:Infant; D007538:Isoniazid / Q000493:pharmacokinetics*; D010641:Phenotype; D012372:ROC Curve
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid