GENOTYPING OF THE ARYLAMINE N-ACETYLTRANSFERASE POLYMORPHISM IN THE PREDICTION OF IDIOSYNCRATIC REACTIONS TO TRIMETHOPRIM-SULFAMETHOXAZOLE IN INFANTS

The pathogenesis of hypersensitivity to trimethoprim-sulfamethoxazole (TMP-SMX) is supposed to be associated with the slow acetylation pheno type; This pharmacogenetic defect is associated with the mutations of the arylamine N-acetyltransferase (NAT2) encoding gene. The aim of the study was to compare the usefulness of the acetylation phenotype and NAT2 coding genotype in the prediction of idiosyncratic reaction to Co trimoxazole in infants. The study was carried out in the group of 20 i nfants, aged 2-12 months (mean age 6.3 months):treated with Cotrimoxaz ole, administered at 100 mg/kg b.w./24 h doses. In seven children (35% ) no adverse effects of the treatment have been observed, whereas in 1 3 (65%) children various adverse effects occurred as a result of the t herapy, such as rash (4 children), granulocytopenia with anemization ( 5 children) or liver impairment (4 children). The acetylation phenotyp e of each child was determined on the basis of urine of N-acetyl isoni azid/isoniazid ratio, after ingestion of isoniazid asa model drug. Fur thermore we used polymerase chain reaction (PCR) followed by the analy sis of restriction fragments length polymorphism (RFLP) technique to i dentify the known mutant alleles of the NAT2 gene. lt has been presume d that the genotype determining fast acetylation contains at least one of wild-type allele. No correlation has been found between the observ ed adverse effects of Cotrimoxazole and age, gender and acetylation ph enotype. However, it has been demonstrated that the risk of adverse ef fects of Cotrimoxazole is considerably higher in children with mutatio ns of the NAT2 encoding gene. The comparison of the results from PCR-R FLP genotyping with phenotyping suggested that in infants, the NAT2 ge notype rather than phenotype provides the basis for the detection of h ypersensitivity to TMP-SMX.