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PubMed2004

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.

Adolescent↗
PubMed2006

Isoniazid's bactericidal activity ceases because of the emergence of resistance, not depletion of Mycobacterium tuberculosis in the log phase of growth.

BACKGROUND: It is believed that the cessation of isoniazid's early bactericidal activity during the initial phase of antituberculosis therapy is due to the depletion of Mycobacterium tuberculosis in the exponential phase of growth. We examined the veracity of this cornerstone belief. METHODS: We used an in vitro infection model in which M. tuberculosis was exposed to isoniazid concentration-time profiles encountered in human patients. Experiments were performed to examine the time-related changes in the total bacterial population, the isoniazid-susceptible subpopulation, and the isoniazid-resistant subpopulation. RESULTS: The cessation of microbial kill occurred between days 3 and 4 of isoniazid therapy, as occurs in patients. There were multiple logs of organisms in the exponential phase of growth remaining at the time when bactericidal activity ceased. The isoniazid-susceptible subpopulation was replaced by an isoniazid-resistant subpopulation after 80 h of therapy. The size of the isoniazid-susceptible subpopulation continued to decrease after the total population had ceased to decrease, whereas the resistant subpopulation remained in the exponential phase of growth. Resistance was due to single point mutations in the catalase-peroxidase gene and to reserpine-inhibitable efflux pumps. CONCLUSIONS: The age-old hypothesis that isoniazid's microbial killing of M. tuberculosis during log-phase growth ceases because of the depletion of this bacillary population needs to be modified.

Antitubercular Agents↗
PubMed1994

Effectiveness of rifabutin alone or in combination with isoniazid in preventive therapy of mouse tuberculosis.

The ever-increasing incidence of tuberculosis calls for the implementation of control measures, including new efficient, short-term preventive therapies to replace 6 to 12 months of isoniazid therapy. The efficacies of 12-week regimens of rifabutin or isoniazid given daily and the combination of the two drugs administered intermittently were evaluated in mice infected with Mycobacterium tuberculosis after vaccination with the bacillus Calmette-Guérin (BCG) to imitate some features of the natural infection in humans with a low number of persisting bacteria. Rifabutin at 10 mg/kg of body weight per day was highly effective as early as the eighth week of treatment: all spleens were sterilized and the number of bacteria was drastically reduced in the lungs (mean +/- standard deviation log CFU, 0.2 +/- 0.3, compared with 5.9 +/- 0.6 for untreated controls). No bacilli were found in the spleens or lungs of any of the animals treated for 12 weeks. The combination of rifabutin at 10 mg/kg plus isoniazid at 25 mg/kg twice weekly was almost as effective as rifabutin daily: after 8 weeks of treatment only two of six mice harbored a small number of mycobacteria in their spleens and lungs; at week 12, all spleens were sterilized and a total of eight colonies were isolated from the lungs of two of six mice. Daily isoniazid and once-weekly rifabutin plus isoniazid therapies were less effective. Colonies randomly isolated from the spleens and lungs of mice from different experimental groups were also tested for their susceptibilities to the two drugs. The three surviving colonies from rifabutin-treated mice and all colonies from those administered rifabutin plus isoniazid remained fully susceptible to either drug. In contrast, 2 (18%) of the 11 colonies randomly selected from isoniazid-treated mice became resistant to isoniazid (MIC, > 2 micrograms/ml), although they were still susceptible to rifabutin. Three months of treatment with rifabutin, either daily alone or twice a week combined with isoniazid, proved to be a valid candidate for tuberculosis preventive therapy.

Animals↗
PubMed2003

Isoniazid activation defects in recombinant Mycobacterium tuberculosis catalase-peroxidase (KatG) mutants evident in InhA inhibitor production.

Mycobacterium tuberculosis KatG catalyzes the activation of the antitubercular agent isoniazid to yield an inhibitor targeting enoyl reductase (InhA). However, no firm biochemical link between many KatG variants and isoniazid resistance has been established. In the present study, six distinct KatG variants identified in clinical Mycobacterium tuberculosis isolates resistant to isoniazid were generated by site-directed mutagenesis, and the recombinant mutant proteins (KatG(A110V), KatG(A139P), KatG(S315N), KatG(L619P), KatG(L634F), and KatG(D735A)) were purified and characterized with respect to their catalase-peroxidase activities (in terms of k(cat)/K(m)), rates of free-radical formation from isoniazid oxidation, and, moreover, abilities to activate isoniazid. The A110V amino acid replacement did not result in significant alteration of KatG activities except that the peroxidase activity was enhanced. The other mutations, however, resulted in modestly reduced catalase and peroxidase catalytic efficiencies and, for the four mutants tested, significantly lower activities to oxidize isoniazid. Compared to the wild-type enzyme, the ability of the KatG(L634F), KatG(A139P), and KatG(D735A) variants to activate isoniazid decreased by 36%, 76%, and 73%, respectively, whereas the KatG(S315N) and KatG(L619P) variants completely lost their abilities to convert isoniazid into the InhA inhibitor. In addition, the inclusion of exogenous Mn(2+) to the isoniazid activation reaction mix significantly improved the ability of wild-type and KatG mutants to produce the InhA inhibitor.

Antitubercular Agents↗
PubMed2005

Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses?

Isoniazid is metabolized by the genetically polymorphic arylamine N-acetyltransferase type 2 (NAT2). A greater number of high-activity alleles are related to increased acetylation capacity and in some reports to low efficacy and toxicity of isoniazid. The objective of this study was to assess individual isoniazid exposure based on NAT2 genotype to predict a personalized therapeutic dose. Isoniazid was administered to 18 healthy Caucasians (age 30 +/- 6 years, body weight 74 +/- 10 kg, five women) in random order as a 200-mg infusion, a 100-mg oral, and a 300-mg oral single dose. For the assessment of NAT2 genotype, common single nucleotide polymorphisms identifying 99.9% of variant alleles were characterized. Noncompartmental pharmacokinetics and compartmental population pharmacokinetics were estimated from isoniazid plasma concentrations until 24 h postdose by high-pressure liquid chromatography. The influence of NAT2 genotype, drug formulation, body weight, and sex on dose-normalized isoniazid pharmacokinetics was assessed by analysis of variance from noncompartmental data and confirmed by population pharmacokinetics. Eight high-activity NAT2*4 alleles were identified. Sex had no effect; the other factors explained 93% of the variability in apparent isoniazid clearance (analysis of variance). NAT2 genotype alone accounted for 88% of variability. Individual isoniazid clearance could be predicted as clearance (liters/hour) = 10 + 9 x (number of NAT2*4 alleles). To achieve similar isoniazid exposure, current standard doses presumably appropriate for patients with one high-activity NAT2 allele may be decreased or increased by approximately 50% for patients with no or two such alleles, respectively. Prospective clinical trials are required to assess the merits of this approach.

Acetylation↗
PubMed1991

Induction of cytochrome P-450-dependent monooxygenases by isoniazid in hamster liver, kidney and lung.

The effects of isoniazid on liver, kidney, and lung monooxygenases were determined using hamsters administered 0.8% of the antituberculosis drug in drinking water. Binding of isoniazid to liver microsomal cytochrome P-450 induced a Type II difference spectrum and the spectral binding was enhanced in hamsters treated with isoniazid. The levels of cytochrome P-450, NADPH-cytochrome c reductase, and cytochrome b5 in the tissues microsomes from isoniazid-treated hamsters were similar to the respective levels in control animals. In the liver, treatment with isoniazid caused 5- and 3-fold induction of aniline hydroxylase and N-nitrosodimethylamine demethylase activities, respectively. The treatment was without effect on hepatic benzo(a)pyrene hydroxylase or 7-ethoxycoumarin O-deethylase activities. In the kidneys, isoniazid treatment caused 6-, 2-fold, and 42% increases in monooxygenase activities toward aniline, N-nitrosodimethylamine, and 7-ethoxycoumarin, respectively. However, the treatment caused a 15% decrease in renal benzo(a)pyrene hydroxylase activity. In the lungs, isoniazid caused a 69% increase in aniline hydroxylase and, in contrast, a 30% decrease in 7-ethoxycoumarin O-deethylase activities. The treatment had no significant effects on pulmonary catalytic activities toward N-nitrosodimethylamine and benzo(a)pyrene. Gel electrophoresis of liver and kidney microsomes from control and isoniazid-treated hamsters revealed that the treatment increased the intensity of a protein band in the P-450 molecular weight region. Immunoblotting of microsomal proteins showed that the protein band induced by isoniazid in the liver, kidney and lung was cross-reactive with antibody raised against ethanol-inducible human liver P-450.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Pharmacokinetics of the toxic hydrazino metabolites formed from isoniazid in humans.

The plasma concentrations of isoniazid and its hydrazino metabolites, acetylisoniazid, acetylhydrazine and diacetylhydrazine, were measured by gas chromatography-mass spectrometry in 12 healthy subjects after the ingestion of 300 mg of isoniazid. The area under the plasma concentration-time curve of acetylisoniazid and diacetylhydrazine increased with increasing rate of acetylation of isoniazid. In contrast, the area under the plasma concentration-time curve of acetylhydrazine, the postulated precursor of a toxic metabolite formed from isoniazid, was greater in slow acetylators. This occurred even though rapid acetylators generated more acetylisoniazid and thus more acetylhydrazine from isoniazid, because the rapid acetylators also acetylated acetylhydrazine faster to diacetylhydrazine than did the slow acetylators. Due to this complex relationship between area under the plasma concentration-time curve of acetylhydrazine and the rate of isoniazid acetylation (i.e., a faster rate of formation of acetylhydrazine is accompanied by a faster clearance to diacetylhydrazine), the rate of acetylation of isoniazid minimally influences the exposure of most patients to acetylhydrazine. This pharmacokinetic analysis, however, also shows that the apparent plasma half-life of acetylhydrazine is about five times longer than the plasma half-life of isoniazid, and thus repeated doses of isoniazid should lead to an accumulation of acetylhydrazine in the slowest acetylators in which the plasma half-life of acetylhydrazine is 20-plus hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1982

Isoniazid perturbation of the pyridine nucleotide cycle of Escherichia coli.

Isogenic strains of Escherichia coli, differing only in their sensitivity/resistance to isoniazid, were compared on the basis of intracellular accumulation of the intermediates of the pyridine nucleotide cycle and a closely related compound, nicotinamide adenine dinucleotide phosphate. Isoniazid treatment was bacteriostatic for the wild type organism and resulted in an exaggerated lag phase followed by a rapid logarithmic growth rate in the isoniazid-resistant strain. Isoniazid treatment of the wild type strain, even in the absence of growth, resulted in a temporal shift of peak pyridine accumulation from early lag phase to early logarithmic phase. The effect of mutation from isoniazid sensitivity to isoniazid resistance was accompanied by this same temporal shift of peak pyridine accumulation. In addition, mutation was accompanied by increases in the peak concentrations, as compared to wild type, of desamidonicotinamide adenine dinucleotide, nicotinamide, nicotinic acid and nicotinamide mononucleotide; the levels of nicotinic acid mononucleotide, nicotinamide adenine dinucleotide phosphate and nicotinamide adenine dinucleotide were decreased. Isoniazid treatment of the isoniazid-resistant strain, even in the absence of bacteriostasis, caused a decrease in the intracellular concentrations of nicotinic acid and nicotinamide and an increase in nicotinic acid mononucleotide. Isoniazid treatment of both the sensitive and resistant strains resulted in the loss of a peak ratio of NADP to NAD which normally occurred in the late logarithmic/early stationary phase of growth in untreated cultures. This denoted a loss of ability to shift from the generation of energy from glycolysis to generation of energy from the hexose monophosphate shunt.

Escherichia coli↗
PubMed2006

Improved adherence and less toxicity with rifampin vs isoniazid for treatment of latent tuberculosis: a retrospective study.

BACKGROUND: Treatment of latent tuberculosis infection (LTBI) is an important aspect of tuberculosis control in the United States, but the effectiveness of this strategy is compromised by poor adherence to the recommended 9-month isoniazid regimen. In this study, we compared treatment completion and clinically recognized adverse drug reactions in patients prescribed 9 months of isoniazid therapy or 4 months of rifampin therapy for LTBI. METHODS: Retrospective chart review of patients who received LTBI treatment at a public health clinic. RESULTS: A total of 770 patients were prescribed 9 months of isoniazid therapy, and 1379 patients were prescribed 4 months of rifampin therapy. The percentages of patients who completed 80% or more of their prescribed treatment were 52.6% and 71.6% in the isoniazid and rifampin groups, respectively (P<.001). In multivariate logistic regression analysis, treatment regimen was independently associated with treatment completion (adjusted odds ratio for treatment completion, 2.88 for rifampin group vs isoniazid group; 95% confidence interval, 2.27-3.66). Clinically recognized adverse reactions resulting in permanent treatment discontinuation occurred in 4.6% and 1.9% of patients in the isoniazid and rifampin groups, respectively (P<.001). Clinically recognized hepatotoxicity was more common in the isoniazid group (1.8%) than in the rifampin group (0.08%, P<.001). CONCLUSIONS: Compared with a 9-month isoniazid regimen, a 4-month rifampin regimen was associated with a higher percentage of patients completing treatment and a lower percentage of patients with clinically recognized adverse reactions. Additional studies are warranted to determine efficacy and effectiveness of rifampin therapy for LTBI.

Adolescent↗
PubMed1976

Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis.

Isoniazid is the most effective and widely used antituberculosis drug. The metabolism of isoniazid is noninducible and the primary metabolic route determining the rate at which isoniazid is eliminated from the body is acetylation. There are large diffrences between individuals in the rates at which isoniazid and certain other hydrazides and some sulfonamides are acetylated. The acetylation of isoniazid is inherited in a simple Mendelian fashion, individuals being either slow, heterozygous rapid, or homozygous rapid acetylators. Improved methods of discriminating between the different phenotypes have recently been described that are also more convenient to use. The proportion of slow acetylators among Japanese and Eskimos is about 10%; among Chinese about 20%; among Caucasians, Negroes, and South Indians about 60%. The results of a series of meticulously controlled clinical trials carried out in India, East Africa, Hong Kong, Singapore, Czechoslovakia, and Britain have shown the isoniazid acetylator status of tuberculosis patients treated with isoniazid-containing regimens is of no prognostic significance when treatment is given on daily basis. It may, however, be of significance when twice-weekly regimens are employed, especially in circumstances in which only a short period of initial daily chemotherapy is given, and where the companion drug employed during the twice-weekly continuation phase is relatively weak. The acetylator phenotype is, however, extremely important in once-weekly treatment, rapid acetylators always having fared considerably worse than slow acetylators on all the regimens evaluated so far. Experimental studies of the action of isoniazid against Mycobacterium tuberculosis in vitro and in vivo have enabled these findings to be understood.

Acetylation↗
PubMed1977

Drug interactions with isoniazid metabolism in rats.

14C-Isoniazid (20 mg/kg po or iv) was administered alone or in combination with aspirin (100 mg/kg po), rifampin (30 mg/kg po), ethambutol (100 mg/kg po), or ethanol (3 g/kg po) to rats. In another experiment, phenobarbital sodium (40 mg/kg/day ip) was administered for 3 days prior to isoniazid. Aspirin and ethanol retarted the rate of isoniazid absorption from the GI tract. None of the drugs significantly altered the 14C-elimination rate from the blood over the first 4 hr. A tissue distribution study showed that changes in the blood levels produced by ethanol were reflected in the other tissues. When isoniazid was given intravenously, ethanol increased the amount of carbon-14 excreted in urine up to 24 hr after dosing; no other changes were observed in the total carbon-14 recovered in urine. Aspirin inhibited the conjugation of isonicotinic acid with glycine. Ethanol increased N-acetylisoniazid excretion and decreased isonicotinic acid excretion. None of the other treatments had more than a slight effect on isoniazid metabolism. Acute doses of isoniazid failed to produce any signs of hepatotoxicity, as judged by measurement of serum transaminase levels. The data do not suggest that any of the drugs studied are likely to potentiate the hepatotoxicity of isoniazid when administered acutely. Isoniazid metabolism in rats differed quantitatively from that reported for humans.

Administration, Oral↗
PubMed1981

Ethambutol plus isoniazid for the treatment of pulmonary tuberculosis--a controlled trial of our regimens.

A controlled clinical trial of 4 regimens was undertaken in patients with bacteriologically positive, newly-diagnosed pulmonary tuberculosis. The regimens were: ethambutol 15 mg/kg plus isoniazid 400 mg, daily (E7H7); ethambutol 45 mg/kg plus isoniazid 15 mg/kg, twice a week (E2H2); ethambutol 90 mg/kg plus isoniazid 15 mg/kg, once a week plus isoniazid 15 mg/kg, mid-way between the weekly doses (E1H2); and ethambutol 90 mg/kg plus isoniazid 15 mg/kg, once a week (E1H1). All patients received streptomycin 1 g plus ethambutol 25 mg/kg body-weight plus isoniazid 400 mg daily for the first 2 weeks. The total duration of treatment was 12 months for all patients. There were 484 patients admitted to the study. After excluding 60 (41 with initial drug resistance to isoniazid), there remain 424 patients (107 E7H7, 101 E2H2, 107 E1H2, 109 E1H1) in the main analyses. The pretreatment characteristics of the 4 groups were broadly similar. A favourable response at 12 months was observed in 96%, 88%, 93% and 75% of patients respectively: the differences between the E1H1 regimen and the other 3 regimens were all significant (P less than or equal to 0.03) as was that between the E7H7 and E2H2 regimens (P = 0.05). Among the slow inactivators of isoniazid, the proportions with a favourable response at one year were similar in the 4 groups (range 95--91%). However, among the rapid inactivators, the proportion with a favourable response in the E1H1 group was only 57%. There was suggestive evidence that the E1H2 regimen was superior to the E2H2 regimen. Of the patients with bacteriologically quiescent disease at 1 year, approximately a half, at random, had no further chemotherapy and were followed up for a 4-year period. Bacteriological relapse requiring retreatment occurred in 15% of 54 E7H7 patients, 26% of 38 E2H2, 33% of 43 E1H2 and 54% of 37 E1H1 patients, a significant difference (P less than 0.001). A final evaluation of long-term (5-year) favourable response achieved by the 12-month regimens was 83% for the E7H7, 63% for the E2H2, 63% for the E1H2 and 33% for the E1H1 regimens. In general, the regimens were well tolerated and the incidence of adverse reactions to the drugs was low. Of the 424 patients, 6 (1.4%) developed a visual disturbance during the year of chemotherapy.

Adolescent↗
PubMedDate not supplied

Genetic effects of isoniazid and the relationship to in vivo and in vitro biotransformation.

The mutagenic activity of isoniazid, N-acetyl-isoniazid and hydrazine dihydrochloride was investigated in S. typhimurium. Isoniazid was found to possess a weak mutagenic activity only in repair-deficient strains TA1535 and TA100 as well as in the plasmid-containing strain TA92 (10-30 mg/plate) in the Ames test without metabolic activation. Addition of microsomal enzymes by S9 mix decreased this direct mutagenic activity. In contrast, preincubation of isoniazid with crude liver homogenate from mice, rats or Syrian golden hamsters for 4 h prior to plating with bacteria liberated a mutagenic compound which is equally active in both repair-deficient and repair wild-type strains (0.5-5 mg/plate). This activation pathway is independent of NADPH, is heat-sensitive and is operative only in a total liver homogenate in suspension. The highest capacity for mutagenic activation was achieved with liver homogenate from hamsters, followed by that from mice and rats. Furthermore, this mutagenic activation is paralleled by formation of hydrazine, as demonstrated in colorimetric measurements with p-dimethylaminobenzaldehyde. N-Acetyl-isoniazid is without mutagenic activity under similar conditions, and liberation of hydrazine was never detected. This means that, besides having a weak direct genetic activity, isoniazid is a promutagen, and formation of hydrazine is the first step in metabolic activation. It is concluded that the genotoxic properties of isoniazid in mammals are primarily determined by the pharmacokinetic behavior of the ultimate reactive metabolite. This result must be taken into consideration in risk assessment performed for mutagenic and carcinogenic properties of isoniazid in man.

Animals↗
PubMed2005

Correlation between isoniazid resistance and superoxide reactivity in mycobacterium tuberculosis KatG.

Isoniazid is an antituberculosis prodrug that requires activation by the catalase-peroxidase (KatG) of Mycobacterium tuberculosis. The activated species, presumed to be an isonicotinoyl radical, couples to NADH forming an isoniazid-NADH adduct that ultimately confers antitubercular activity. We have compared the catalytic properties of three KatGs associated with isoniazid resistance (resistance mutation KatGs, (RM)KatGs: R104L, H108Q, S315T) to wild-type enzyme and two additional lab mutations (wild-type phenotype KatGs, (WTP)KatGs: WT KatG, Y229F, R418L). Neither catalase nor peroxidase activities, nor the presence/absence of the Met-Tyr-Trp cross-link (as probed by LC/MS on tryptic digests of the protein), exhibited any correlation with isoniazid resistance. The yields of isoniazid-NADH adduct formed were determined to be 1-5, 4-12, and 20-70-fold greater for the (WTP)KatGs than the (RM)KatGs for the compound I, II, and III pathways, respectively, strongly suggesting a role for oxyferrous KatG (supported by superoxide consumption measurements) that correlates with drug resistance. Stopped-flow UV-visible spectroscopic studies revealed that all KatGs were capable of forming both compound II and III intermediates. Rates of compound II decay were accelerated 4-12-fold in the presence of isoniazid (vs absence) for the (WTP)KatGs but were unaffected by the drug for the (RM)KatGs. A mechanism for isoniazid resistance which accounts for the observed reactivity for each of the compound I, II, and III intermediates is proposed and suggests that the compound III pathway may be the primary factor in determining overall isoniazid resistance by specific KatG mutants, with secondary contributions arising from the compound I and II pathways.

Bacterial Proteins↗
PubMed1985

Oxidation of hydrazine metabolites formed from isoniazid.

Studies in rats indicate that the metabolic activation of acetylhydrazine, a metabolite of isoniazid, is a critical determinant of the hepatotoxicity of isoniazid. As demonstrated in that model, the formation of 14CO2 after the administration of 14C-acetylisoniazid reflects the activity of the toxic pathway. A similar approach in man should make it possible to demonstrate the presence and to assess the quantitative importance of this toxifying pathway, and thus to evaluate its role in the pathogenesis of isoniazid hepatitis. We gave 300 mg isoniazid together with 10 microCi 14C-acetylisoniazid (12 mg) to 17 healthy subjects and determined the time course of the plasma concentrations of isoniazid, acetylisoniazid, acetylhydrazine, and diacetylhydrazine and of the exhalation of 14CO2. The time course of 14CO2 in breath closely paralleled the plasma concentration-time curve of acetylhydrazine but not those of acetylisoniazid or diacetylhydrazine, indicating that the 14CO2 originated directly from the metabolism of acetylhydrazine. The cumulative exhalation of 14CO2 increased with decreasing rate of acetylation of isoniazid, such that slow acetylators generated more 14CO2 than rapid acetylators. Simulation studies demonstrated that even if the data are corrected for the different formation of acetylisoniazid from isoniazid in slow and rapid acetylators, the slow acetylators still generated more 14CO2. The data therefore indicate that a substantial fraction of the acetylhydrazine formed from isoniazid passes through a pathway that has been shown in animals to generate highly reactive and hepatotoxic intermediates.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1995

Catalase expression, katG, and MIC of isoniazid for Mycobacterium tuberculosis isolates from São Paulo, Brazil.

The MIC of isoniazid, peroxidase-catalase expression, and the presence of the katG gene for 102 Mycobacterium tuberculosis isolates from patients in São Paulo were compared. Fifty-three isoniazid-resistant and 49 isoniazid-sensitive isolates were analyzed by polymerase chain reaction (PCR) for the presence of katG sequences. All isoniazid-sensitive and 43 (81%) isoniazid-resistant isolates expressed catalase (P = .001). None of isoniazid-sensitive and 4 (7%) of 53 isoniazid-resistant isolates lacked katG sequences. Among 6 isolates with MICs > 50 micrograms/mL, 5 (83%) did not express catalase and 2 lacked katG sequences; only 1 had complete gene deletion shown by Southern blot analysis. These findings indicate a correlation between loss of catalase and isoniazid resistance among highly resistant isolates, but these isolates were a small proportion of resistant clinical M. tuberculosis isolates from São Paulo.

Bacterial Proteins↗
PubMed1999

Isoniazid drug and food interactions.

Isoniazid inhibits the metabolism of several drugs, resulting in clinically significant interactions in some patients. Clinical trials and case reports have documented that isoniazid can cause increased phenytoin and carbamazepine serum concentrations and toxicity. In relatively high doses, isoniazid can also cause increased effect of theophylline and warfarin. Isoniazid inhibits metabolism of selected benzodiazepines and vitamin D. Inhibition of monoamine oxidase and histaminase by isoniazid can cause significant drug-food interactions. Food greatly decreases isoniazid bioavailability. Although probably best recognized as an inhibitor of drug metabolism, isoniazid has a biphasic effect of inhibition-induction on one cytochrome P450 isozyme, CYP2E1, which partially explains the interaction with acetaminophen and increased risk of hepatotoxicity. Continued investigations will likely result in discovery of new isoniazid interactions.

Antitubercular Agents↗
PubMed1991

Inhibition of the metabolism of paracetamol by isoniazid.

1. The effect of isoniazid given daily for 7 days on paracetamol (acetaminophen) kinetics and metabolism was studied in 10 healthy volunteers. Paracetamol, 500 mg, was given before isoniazid, on day 7 of isoniazid administration, and 2 days after the last dose of isoniazid. 2. On day 7, isoniazid markedly inhibited the formation clearance of the glutathione and catechol metabolites by 69.7% and 62.2%, respectively. Total paracetamol clearance was lowered by 15.2%. There was no effect of isoniazid on the non-oxidative pathways of paracetamol elimination. 3. Two days after isoniazid was discontinued, paracetamol metabolism had returned to pre-isoniazid values.

Acetaminophen↗