Acetylator phenotype and metabolic disposition of isoniazid in japanese patients with systemic lupus erythematosus

Ishizaki, Takashi; Horai, Yukio; Koya, Gyoichi; Matsuyama, Kenji; Iguchi, Sadao

doi:10.1002/art.1780241004

Cited by 16 publications

(7 citation statements)

References 46 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, the techniques of determining acetylator phenotype have varied among the earlier studies, with two groups of investigators using INH (Larsson et al, 1977;Fishbein & Alarc6n-Segovia, 1979), three dapsone (Reidenberg & Martin, 1974;Vansant et al, 1978;Morris-.et al, 1977), three sulphamethazine (Johansson etal., 1976;Foad et al, 1977;Lawson et al, 1979), and one INH or dapsone (Reidenberg et al, 1980 (Drayer & Reidenberg, 1977;Lunde et al, 1977), it is unlikely that this is a possible variable that could explain the discrepancy. However, our patients, except for one, received corticosteroid therapy and had variable serological activity when studied (Ishizaki et al, 1981). Vansant et al (1978) reported that there was no significant correlation between the acetylation phenotype and the prednisone dose or the anti-DNA antibody.…”

Section: Discussionmentioning

confidence: 99%

“…The distribution of the phenotypes classified by the method of Scott et al (1969) and the individual variation of INH and its metabolites excreted in urine are described elsewhere (Ishizaki et al, 1981). (Ishizaki et al, 1981). Briefly, all patients met four or more of the American Rheumatism Association criteria for SLE (Cohen et al, 1971); none had received procainamide, hydralazine, isoniazid, anticonvulsants, or other drugs incriminated as causes of the lupus syndrome (Drayer & Reidenberg, 1977;Lunde etal., 1977) prior to the diagnosis of the disease; there were 16 females and 3 males whose ages ranged from 17 to 47 (mean 29.5) years and their body weights ranged from 44 to 68 (mean 52.2) kg; eighteen patients were receiving corticosteroid therapy and under the treatment, all patients were clinically stable when studied.…”

Section: Introductionmentioning

confidence: 99%

“…We have taken this advantage. The distribution of the phenotypes classified by the method of Scott et al (1969) and the individual variation of INH and its metabolites excreted in urine are described elsewhere (Ishizaki et al, 1981). (Ishizaki et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Isoniazid disposition, comparison of isoniazid phenotyping methods in and acetylator distribution of Japanese patients with idiopathic systemic lupus erythematosus and control subjects.

Horai¹,

Ishizaki²,

Sasaki³

et al. 1982

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 Plasma levels of isoniazid (INH) and acetyl INH in plasma were measured with a spectrofluorometric method, and INH and its metabolites (acetyl INH, mono‐acetylhydrazine, diacetylhydrazine and free hydrazine) excreted in urine were measured with a gas chromatography‐ mass spectrometry, respectively, after an oral dose of INH 10 mg/kg in 19 Japanese patients with idiopathic systemic lupus erythematosus (SLE) and in the same number of healthy controls. 2 When phenotyped according to various methods previously reported, 16 to 18 of the SLE and 17 to 19 of the control group were rapid acetylators. Regardless of the phenotyping methods applied, the distribution of acetylator phenotype of SLE patients was not significantly different from the control group or from the data previously reported among normal Japanese population. 3 By phenotyping our subjects with an INH T 1/2 of 110 min or less as rapid acetylators, and more slow acetylators, 3 of SLE patients and 2 of the controls were slow, while the remainder were all rapid. When this antimode was used, the mean apparent kinetic variables of INH and acetyl INH estimated from the plasma concentration‐time data and the mean values for the 24‐h urinary amount of INH and its metabolites, except for monoacetylhydrazine (P less than 0.05), did not significantly differ between the rapid acetylators of SLE and control groups. 4 The distribution of INH T 1/2, acetyl INH to INH ratios in plasma and urine, values in urine for log10 (diacetylhydrazine to monoacetylhydrazine) and for diacetylhydrazine to INH or acetyl INH was similar between the two groups except for one patient who was definitely classified as a slow acetylator regardless of whichever phenotyping methods were used. The excretory patterns of hydrazine compounds reflect, in general, the inactivating ability of INH in each individual. 5 The data suggest that phenotyping by using plasma samples is, in general, better than by using urine samples. The plasma T 1/2 alone is the most satisfactory criterion. 6 We conclude that neither INH disposition nor phenotype distribution assessed by the reported methods using INH as the test compound are altered in idiopathic SLE, and that a search for racial and/or geographical factor(s) likely to result in autoimmune disease may give a clue to the pathogenesis in addition to further exploration for the possible interrelation between idiopathic SLE and genetic slow acetylation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Isoniazid disposition, comparison of isoniazid phenotyping methods in and acetylator distribution of Japanese patients with idiopathic systemic lupus erythematosus and control subjects.

Horai¹,

Ishizaki²,

Sasaki³

et al. 1982

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…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.…”

mentioning

confidence: 99%

N-Acetyltransferase2 Genotype Correlated with Isoniazid Acetylation in Japanese Tuberculous Patients.

Kita

Tanigawara

Chikazawa

et al. 2001

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

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 ...

show abstract

“…Because of recent interest in the possible involvement of Hz as a mutagen [2], in the aetiology of drug-induced systemic lupus erythematosis [3] and hepatotoxicity in TB patients [4,5,6, 7] the available data on Hz levels and kinetics in children were assembled. Examination of the results suggested a possible connexion between an abnormally large hydrazine accumulation and episodes of hepatotoxicity.…”

mentioning

confidence: 99%

Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients

Gent

Seifart

Parkin

et al. 1992

Eur J Clin Pharmacol

View full text Add to dashboard Cite

An HPLC method is described for measurement of plasma hydrazine (Hz) concentrations (CHz) at the same time as isoniazid (INH) levels (CINH). Study has been made of CHz during 2-5 after dose in healthy adults (A, n = 34), in adult pulmonary TB patients (B, n = 18) and in paediatric tuberculous meningitis patients (C, n = 25). Although the population has about equal proportions of 'slow' (52%) and 'fast' acetylators, in none of the groups could a correlation be shown between CHz levels or rates of Hz accumulation and any measure of acetylator type. Consequently Hz must be derived both from INH and from its metabolites during the first hours post-dose. For group A and ca. 70% of groups B and C a constant and maximal fraction of dose (ca. 0.6% for adults and 0.4% for paediatric patients) appeared as Hz at 4-5 h. For group B patients small pre-dose concentrations increased with duration of treatment. Four patients in group B showed the highest levels of CHz and rates of Hz accumulation some three times greater than the rest; all four had been identified as alcoholics and one showed evidence of hepatotoxicity at CHz (5 h) = 1.3% of dose. Amongst group C (9/25) episodes of high CHz greater than 0.5% of dose occurred during the first weeks of treatment and one developed CHz ca. 100 ng/ml = 1.3% of dose coincidentally with indications of hepatic damage.

show abstract

Acetylator phenotype and metabolic disposition of isoniazid in japanese patients with systemic lupus erythematosus

Cited by 16 publications

References 46 publications

Isoniazid disposition, comparison of isoniazid phenotyping methods in and acetylator distribution of Japanese patients with idiopathic systemic lupus erythematosus and control subjects.

Isoniazid disposition, comparison of isoniazid phenotyping methods in and acetylator distribution of Japanese patients with idiopathic systemic lupus erythematosus and control subjects.

N-Acetyltransferase2 Genotype Correlated with Isoniazid Acetylation in Japanese Tuberculous Patients.

Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients

Contact Info

Product

Resources

About