In the early 1950s, isoniazid (INH) was developed as chemotherapeutic agent for the treatment of tuberculosis.
2)However, serious side effects including peripheral neuritis and hepatic toxicity were recognized in some patients, despite their dosage being similar to that taken by others. Previous studies indicated that INH was catabolized to inactive Nacetylisoniazid (AcINH) by N-acetyltransferase2 (NAT2) (Fig. 1), and that the interindividual variation of plasma concentration and urinary recovery of INH were characterized by a bimodal or trimodal distribution. 3,4) N-acetylation of INH is reported to be genetically determined in a simple Mendelian fashion, and the frequencies of rapid (and/or intermediate) and slow acetylator of INH is different among racial populations. 5) There have been studies on the relationships between the acetylator phenotype and the efficacy or side effects of INH. The rapid acetylators should take larger doses of INH than slow acetylators, 6) and slow acetylators are at risk of adverse reactions such as peripheral neuritis, 4) hepatic toxicity 4,7) and systemic lupus erythematosus-like syndromes.8,9) These findings strongly suggested the necessity of therapeutic drug monitoring (TDM) in blood or serum to define the most appropriate dosage regimen for each individual. 10,11) Recently, Deguchi and his colleagues defined four NAT2 alleles, the wild-type allele (NAT2*4) and three mutant alleles (NAT2*5B, NAT2*6A and NAT2*7B), which could explain 93-97.5% of the trimodal INH acetylator phenotype among Japanese healthy subjects.12,13) An individual INH N-acetyltransferase2 (NAT2). In the present study, the relationship between the NAT2 genotype and the INH acetylator phenotype was examined in Japanese tuberculous patients and compared with healthy subjects. Subjects were classified according to the genotyping into NAT2*5B (allele4), NAT2*6A (allele3) and NAT2*7B (allele2), using the PCR-RFLP method. Twelve healthy subjects and 7 tuberculous patients participated in the INH acetylator phenotyping study, in which each subject was administered an oral dose of INH, followed by urine sampling for 24 h. Urinary concentrations of INH and N-acetylisoniazid (AcINH) were measured by the HPLC method. The urinary recoveries of INH (% of dose) in healthy subjects in relation to NAT2 genotyping were as follows: 6.4؎2.2 in the homozygotes for the wild-type allele, 10.7؎ 2.2 in the compound heterozygotes for the mutant allele, and 38.6؎6.4 in the homozygotes for the mutant allele. In the patients study, the findings in the corresponding three groups were 4.0؎1.7, 8.8 and 18.3؎9.3. Although no significant difference was found because of the lower systemic exposure of INH in patients compared with healthy subjects, there were differences in the disposition kinetics of INH between subjects with and without mutations in the NAT2 gene, and these findings were observed not only in healthy subjects but also in patients who had comedicated drugs and hepatic dysfunctions. The findings indicated that the metabolism ...