Synthetic Tuberculostats. VIII. Acyl Derivatives of Isonicotinyl Hydrazine

Fox, H. Herbert; Gibas, John T.

doi:10.1021/jo50016a018

Cited by 43 publications

(21 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AcINH was synthesized by the method of Fox and Gibas. 16) Five kinds of polymerase chain reaction (PCR) primers for NAT2 genotyping were synthesized by Rikaken Co. (Nagoya, Japan). 14) All other chemicals were of reagent grades and obtained commercially.…”

Section: Methodsmentioning

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

Section: Methodsmentioning

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

show abstract

“…The intact INH and its metabolites in urine, acetyl INH, mono-acetylhydrazine, diacetylhydrazine and free hydrazine, were analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The details are described in the previous reports by Noda et al, (1978 (Fox & Gibas, 1953;Turner, 1947). Briefly, unchanged INH, acetyl INH and diacetylhydrazine were assayed by using BAH as the internal standard on a glass column (1 m x 3 mm, i.d.)…”

Section: Analysis Of Urinary Metabolitesmentioning

confidence: 99%

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

“…Nicotinohydrazide was prepared by the reaction of ethyl nicotinate on hydrazine monohydrhydrate at reflux in the EtOH solution for overnight [17]. After the reaction was completed, the corresponding compound nicotinohydrazide was provided as a white solid in 80% yield.…”

Section: Resultsmentioning

confidence: 99%

“…• C in i-PrOH solution for 2 h [17]. The solid product was formed and the hot-filtration was performed to isolate the crude 1,3,4-oxadiazoletriazolopyridinone-carbazole derivatives 4a-4c.…”

Section: Resultsmentioning

confidence: 99%

New synthesis of highly potential efficient bluish-green electroluminescent materials based on 1,3,4-oxadiazole–triazolopyridinone–carbazole derivatives for single-layer devices

et al. 2006

View full text Add to dashboard Cite

show abstract

Synthetic Tuberculostats. VIII. Acyl Derivatives of Isonicotinyl Hydrazine

Cited by 43 publications

References 4 publications

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

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

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

New synthesis of highly potential efficient bluish-green electroluminescent materials based on 1,3,4-oxadiazole–triazolopyridinone–carbazole derivatives for single-layer devices

Contact Info

Product

Resources

About