The influence of human N-acetyltransferase genotype on the early bactericidal activity of isoniazid.
The elimination of isoniazid is subject to the influence of the N-acetyltransferase 2 (NAT2) genotype, and individuals may be homozygotic slow, heterozygotic fast, or homozygotic fast acetylators of isoniazid. The early bactericidal activity (EBA) of an antituberculosis agent can be determined by quantitative culture of Mycobacterium tuberculosis in sputum samples obtained from patients with pulmonary tuberculosis during the first days of treatment. In these studies, the EBA of isoniazid during the first 2 days of treatment was determined for 97 patients with sputum smear-positive pulmonary tuberculosis following isoniazid doses of < or =37.5 mg, 75 mg, 150 mg, 300 mg, and 600 mg. The NAT2 genotype was determined in 70 patients, and the association between EBA and genotype was examined in this subgroup. Similarly, the relationship between EBA and isoniazid serum concentration was evaluated in 87 patients. The mean EBA of isoniazid increased with dose, but it levelled off between doses of 150 mg (mean EBA, 0.572) and 300 mg (mean EBA, 0.553). Significant differences were found in the mean EBA of isoniazid between the homozygous slow acetylator group and the heterozygous fast acetylator group and between the homozygous slow acetylator group and the homozygous fast acetylator group, but not between the heterozygous fast acetylator group and the homozygous fast acetylator group. The EBA appeared to reach a maximum at a 2-h isoniazid concentration of 2-3 microg/mL. These data confirm a significant effect of NAT2 genotype on the EBA of isoniazid over a range of doses.
Donald
P R
PR
Department of Paediatrics and Child Health, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa. prd@sun.ac.za
Sirgel
F A
FA
Venter
A
A
Parkin
D P
DP
Seifart
H I
HI
van de Wal
B W
BW
Werely
C
C
van Helden
P D
PD
Maritz
J S
JS
D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000378:metabolism* / Q000494:pharmacology*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology*
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid