Trimodality of isoniazid elimination: phenotype and genotype in patients with tuberculosis.

Abstract

The study was undertaken to show that polymorphic isoniazid elimination in humans is trimodal; that the acetylator genotype and eliminator phenotype of the individual patient are concordant; and that the differences in the pharmacokinetic parameters of fast, intermediate, and slow eliminator subgroups are statistically significant. Sixty adult patients of both sexes and of mixed race with tuberculosis participated in the trial. The apparent elimination rate constant (k, h(-1)) and the area under the isoniazid concentration-time curve (AUC, mg/L/h), over the interval 2 to 6 h after oral isoniazid were determined in all patients; NAT2 allele composition was determined in 47 patients. Serum INH concentrations were determined by HPLC and genotypes by PCR/restriction enzyme analysis. Three eliminator phenotypes could be distinguished, and concordance between the phenotype and the genotype of the individual could be demonstrated. The isoniazid concentration-time profiles of the three eliminator subgroups were significantly different (p < 0.05). The NAT2*12A allele, which codes for fast acetylation, has a high frequency in the population studied, the intermediate acetylator genotype is constituted of codominant fast and slow alleles, and the distribution of phenotypes/genotypes in the population is consistent with Hardy-Weinberg predictions. The therapeutic implications of polymorphic isoniazid metabolism are discussed.

N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk

“…This trimodal distribution of rapid, intermediate and slow acetylator phenotypes in Syrian hamsters congenic at NAT2 also is clearly evident in vivo (Figure 2). Although many human studies often exhibit bimodal distributions of rapid and slow acetylator NAT2 phenotypes, studies with hydrazine drugs such as isoniazid (Parkin et al, 1997;Smith et al, 1997), aromatic amine drugs such as sulfamethazine (Chapron et al, 1980;Lee and Lee, 1982) and caffeine, a compound with a metabolite that is N-acetylated Gross et al, 1999;Grant et al, 2004), yield rapid, intermediate and slow acetylator phenotypes. The unequivocal detection of three phenotypes can be confounded by various factors including catalysis by NAT1.…”

“…The other studies did not distinguish the NAT2*12 or the NAT2*13 allele from NAT2 genotypes that do not possess NAT2*12 or NAT2*13. Nevertheless, verification of NAT2*12 and NAT2*13 as rapid acetylator alleles has been provided in vivo Parkin et al, 1997). The latter study (Parkin et al, 1997) included five subjects possessing the NAT2*13 allele and 20 subjects possessing the NAT2*12A allele that consistently confirmed rapid acetylator status based upon measured phenotypes in several people.…”

“…Nevertheless, verification of NAT2*12 and NAT2*13 as rapid acetylator alleles has been provided in vivo Parkin et al, 1997). The latter study (Parkin et al, 1997) included five subjects possessing the NAT2*13 allele and 20 subjects possessing the NAT2*12A allele that consistently confirmed rapid acetylator status based upon measured phenotypes in several people. Recombinant NAT2 proteins differ in heat stability (Ferguson et al, 1994;Hein et al, 1994b;Grant et al, 1997;Leff et al, 1999;Fretland et al, 2001).…”

Détermination du polymorphisme d’acétylation de la N-acétyltransférase 2 dans la population sénégalaise par utilisation du test à la caféine

“…Le polymorphisme de la NAT2 (36 variants alléliques) se traduit par l'expression de phénotypes dits « acétyleurs lents » et « acétyleurs rapides » [7][8][9][10][11]. De très grandes variations interethniques dans la fréquence des acétyleurs lents sont dé-crites.…”

“…Chez les acétyleurs rapides, on peut craindre un risque accru d'échecs thérapeutiques mais surtout un risque plus important d'hépatotoxicité liée à la surproduction d'un métabolite hépatotoxique de l'isoniazide qui est l'acétylhydra-zyl [25]. Il a également été décrit un phénotype d'acétyleurs intermédiaires de la NAT2 classant ainsi les sujets en trois populations différentes selon le profil d'acétylation [7,26].…”