INTRODUCTION — Isoniazid (INH; isonicotinylhydrazide or isonicotinic acid hydrazine) is a synthetic antibiotic that is potently bactericidal against replicating Mycobacterium tuberculosis. INH has since been associated with two syndromes of hepatotoxicity: mild INH hepatotoxicity and INH hepatitis [1-3].
Issues related to INH hepatotoxicity will be reviewed here. The clinical use of INH is discussed separately. (See "Treatment of latent tuberculosis infection in HIV-uninfected nonpregnant adults" and "Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults".)
MILD INH HEPATOTOXICITY — Mild INH hepatotoxicity refers to hepatic injury that is typically subclinical, asymptomatic, and evidenced only by mildly elevated serum aminotransferases (usually <100 international units/L) [4-6]. It occurs in up to 20 percent of patients treated with INH [7-11].
Adults are more likely to be affected than children; males and females appear to be equally vulnerable. There is no relationship to race or the rate of hepatic acetylation of the drug.
Most cases are self-limited; in general, INH therapy can be continued with careful monitoring in the absence of dose adjustment. Typically, aminotransferase levels return to normal within several weeks after discontinuation of INH [12,13].
INH HEPATITIS — INH hepatitis is a more serious clinically apparent liver injury syndrome; it is usually symptomatic and may be fatal [14,15]. It is an idiosyncratic reaction that is not clearly related to dose or duration of therapy.
Prevalence and risk factors — The risk of INH hepatitis associated with INH therapy for treatment of latent tuberculosis is 0.5 to 1.0 percent; INH hepatitis is fatal in 0.05 to 0.1 percent of cases [6,16-21].
Risk factors for the development of hepatotoxicity include [6,17,22-31]:
●Increased age [17,32-34] with an odds ratio for adverse events of 1.8 for individuals 35 to 64 years and 3.0 for individuals aged 65 to 90 years [35].
●Regular alcohol intake [17,23]. It is possible that the use of alcohol may increase the risk of hepatotoxicity. One study noted development of hepatitis in 2.6 percent of patients treated with INH who drank alcohol daily [36].
●Concurrent use of medications that induce CYP (P450) oxidative enzymes (table 1) and/or are themselves hepatotoxic (eg pyrazinamide, acetaminophen-containing preparations, lipid-lowering agents, herbal supplements, and others) [1,37,38].
●Previous INH intolerance (eg, headaches, dizziness, nausea). Rechallenge with INH may result in recurrence of hepatotoxicity; however, some studies have shown that up to 80 percent of persons may be able to tolerate reintroduction of the drug [39,40].
●Prior or concurrent liver disease, such as chronic viral hepatitis [37,41-43]. In one study of Vietnamese patients with hepatitis B treated with INH for latent tuberculosis infection, patients with HBeAg positivity were more likely to develop severe INH toxicity than patients who were HBeAg negative [42]. However, other studies have not observed an association between chronic viral hepatitis and risk for INH hepatotoxicity [44].
●History of peripheral neuropathy or presence of risk factors for peripheral neuropathy (eg, due to diabetes mellitus or alcoholism).
●Pregnancy and the immediate postpartum period with an odds ratio for hepatoxicity of 1.64 [45]. However, the data regarding risk to pregnancy outcomes remain inconsistent.
●Injection drug use.
●Female sex [32,46,47].
●Genetic predisposition (including acetylator status), particularly with three variant alleles on the NAT2 gene: position 481C>T, position 590G>A, and position 857G>A [48-52]. Testing for NAT2 polymorphisms may allow for adjustment in drug dosing to improve therapeutic effect and to reduce toxicity [53-57]. (See 'Mechanism of hepatotoxicity' below.)
●Severely immunocompromised patients with advanced HIV infection [58].
Clinical manifestations — Clinical manifestations of INH hepatitis typically occur within the first two to three months after initiation of therapy; they can occur as late as 14 months after initiation of therapy [6,13,17,22].
Clinical manifestations include fatigue, malaise, anorexia, and/or nausea, with or without vomiting. Approximately one-third of patients have generalized flu-like symptoms, and some have right upper quadrant pain. Liver injury is typically hepatocellular; however, jaundice is a presenting feature in approximately 10 percent of cases and manifests days to weeks after onset of the above symptoms [22,59].
INH hepatitis may be associated with the development of hepatocellular necrosis and acute liver failure in up to 1 to 3 percent of cases; clinical manifestations may include ascites, edema, and encephalopathy [6,17,32]. The physical examination is largely nonspecific. Jaundice and abdominal pain may be present. Fever, rash, lymphadenopathy, and hepatomegaly are uncommon.
Laboratory evaluation characteristically demonstrates elevated aminotransferases (may be >10 times the upper limit of normal [ULN]) and variable elevations in alkaline phosphatase (usually <2 times ULN), bilirubin, and prothrombin time [32].
Histologically, liver injury is predominantly hepatocellular in nature and ranges from focal mononuclear cell infiltrate to diffuse massive necrosis [13,59,60].
Diagnosis — The diagnosis of INH hepatitis should be suspected in patients taking INH who develop fatigue, malaise, anorexia, nausea, and/or vomiting in association with elevated serum aminotransferases. The diagnosis is established clinically, based on clinical manifestations and exclusion of other causes; the diagnosis is supported by resolution of elevated aminotransferases within several weeks after discontinuation of therapy [3].
There is overlap in the pattern of liver injury caused by INH and other antituberculosis agents including rifampin and pyrazinamide; all individually or in combination may contribute to hepatotoxicity.
Clinical evaluation of patients with suspected INH hepatitis should include clinical history regarding alcohol use and exposure to other potential hepatotoxins. Laboratory evaluation should include testing for viral hepatitis and autoimmune hepatitis. (See 'Differential diagnosis' below.)
Additional issues related to diagnostic evaluation of drug-induced liver injury are discussed separately. (See "Drug-induced liver injury", section on 'Diagnosis'.)
Differential diagnosis — The differential diagnosis of INH hepatitis includes other causes of elevated aminotransferases (see "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated serum aminotransferases'):
●Viral hepatitis – Viral hepatitis can occur as a result of infection due to hepatitis A, B, C, D, E, Epstein-Barr virus, cytomegalovirus, HIV, or other viral infections. The clinical manifestations include fatigue, malaise, anorexia, nausea, and/or vomiting. The diagnosis is established via serology. (See related topics).
●Drug-induced liver injury – Drug-induced liver injury associated with medications or herbal therapies may present with mild, asymptomatic liver test abnormalities, cholestasis with pruritus, acute jaundice, or acute liver failure. The diagnosis is established clinically. (See "Drug-induced liver injury".)
●Autoimmune hepatitis – Clinical manifestations of autoimmune hepatitis include fatigue, anorexia, nausea, abdominal pain, and itching. INH can induce development antinuclear antibodies, even without hepatotoxicity. In the setting of INH hepatitis, autoantibody titers are generally low and hyperglobulinemia is not seen, which helps to differentiate it from autoimmune hepatitis. The diagnosis of autoimmune hepatitis is based upon characteristic serologic and histologic findings. (See "Overview of autoimmune hepatitis".)
●Ischemic injury – Ischemic hepatitis refers to diffuse hepatic injury resulting from acute hypoperfusion. Most patients have no symptoms referable to the liver but have marked elevation of the serum aminotransferase levels (exceeding 1000 international units/L or 50 times the upper limit of normal) after an episode of hypotension. (See "Ischemic hepatitis, hepatic infarction, and ischemic cholangiopathy".)
Management — Management of INH hepatitis consists of early recognition with timely discontinuation of INH and other potential hepatotoxins [6]. In severe cases, liver transplantation may be required [17,61].
In general, hepatitis attributed to antituberculosis drugs should prompt discontinuation of all hepatotoxic drugs if the serum bilirubin is ≥3 mg/dL or serum transaminases are more than five times the upper limit of normal (algorithm 1) [1,3].
Once liver function tests return to baseline (or fall to less than twice normal), potentially hepatotoxic drugs can be restarted one at a time with careful monitoring between resumption of each agent (algorithm 1). (See "Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults".)
The approach to regimen adjustment for drug intolerance is discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults", section on 'Regimen adjustments for drug intolerance'.)
Prevention — Use of INH should be limited to appropriate clinical circumstances, and patients should be educated about the signs and symptoms of hepatic toxicity; should toxicity be suspected, patients should be instructed to stop the medication and contact their provider [3,17,62].
Interest exists in development of newer formulations of INH which are less toxic. Examples include a cocrystal formulation (INH-quercetin), hydrazide and aurone derivatives, and INH-a (INH-benzaldehyde) [63-66].
Issues related to clinical and laboratory monitoring for patients on INH for treatment of latent tuberculosis infection are discussed separately. (See "Treatment of latent tuberculosis infection in nonpregnant adults with HIV infection", section on 'Monitoring and adherence'.)
Issues related to clinical and laboratory monitoring for patients on INH and other antituberculous drugs for treatment of active tuberculosis infection are discussed separately. (See "Antituberculous drugs: An overview", section on 'Clinical and laboratory monitoring'.)
Prognosis — The overall case-fatality rate in patients who develop clinically apparent hepatitis is approximately 10 percent [22]. Older adult patients or those who present with INH hepatitis after taking the drug for more than two months have a worse prognosis [5,22,67,68]. Some studies have found a higher case-fatality rate among African-American patients than other patients, as well as a higher case-fatality rate among African-American females than African-American males [22,29,69-71].
MECHANISM OF HEPATOTOXICITY — The mechanism of INH hepatotoxicity remains incompletely understood [72]. Toxicity is likely associated with metabolism of the drug [22,72-74]. Alternatively, liver injury may occur via induction of an immune response that causes liver injury [75,76].
INH is rapidly absorbed from the gastrointestinal tract and diffuses into all body tissues [77]. The presence of food in the stomach significantly hinders absorption [78]. The plasma concentration reaches its peak approximately one to three hours after ingestion of the medication [72]. Hepatic metabolism of INH creates numerous metabolites including isonicotinic acid (INA), hydrazine (HZ), ammonia, N1-acetyl-N2-isonicotinylhydrazide (AcINH or acetylINH), acetylhydrazine (AcHZ), diacetylhydrazine (DiAcHZ), and oxidizing free radicals [79]. These compounds are formed via three predominant reactions [80]:
●Acyl amidase hydrolysis – Forming INA and HZ
●Cytochrome P450 oxidation – Forming HZ, ammonia, and free radicals
●N-acetyltransferase 2 (NAT2) activity – Forming AcINH, AcHZ, and DiAcHZ
AcHZ, toxic free radicals, and particularly hydrazine are the drug metabolites that have been most consistently implicated in the pathogenesis of INH hepatitis [81,82]. INH is first acetylated within the liver via NAT2 to form the inactive compound AcINH, which is then hydrolyzed to form AcHZ and INA [79]. AcHZ is usually further acetylated to the nontoxic derivative DiAcHZ and excreted in the urine [15]. It is also oxidized into ammonia by the liver, with contributions from the muscle, kidney, and brain [79]. In addition, AcHZ can be oxidized by the cytochrome P450 pathway to form toxic reactive acetyl free radicals that can form covalent bonds with liver cell macromolecules, interfering with their function and leading to hepatocellular necrosis and cell death [5,7,48,73,81,83-85]. Cytochrome isoforms 2E1, 2B1, and 1A1/A2 have been implicated in this process [86-88].
NAT2 is a phase II enzyme and is the primary enzyme involved in the metabolism of INH [52]. Deficiency of this enzyme has been associated with INH hepatotoxicity. The exact mechanism by which the NAT2 deficiency may cause hepatotoxicity is not known [72]. NAT2 is highly polymorphic, and these genetic polymorphisms are associated with trimodal pharmacokinetics of INH with three phenotypes: slow, intermediate, and fast acetylation [89-93]. The NAT2 polymorphisms significantly affect the plasma concentrations of INH, with fast acetylators having lower plasma concentrations than slow acetylators [94,95]. (See "Drugs and the liver: Metabolism and mechanisms of injury".)
Data on the association between acetylator phenotype and risk of INH hepatotoxicity have been conflicting [8,25,27,67,80,84,96-105]. Rapid acetylation of AcHZ should in theory reduce the formation of toxic AcHZ oxidative metabolites [48]. Studies have also suggested a higher rate of toxicity in slow acetylators carrying homozygous mutant alleles, leading to a higher concentration of AcHZ [48-50,93,100,106,107]. Meta-analysis has shown that genetic variants of NAT2 play a role in INH hepatotoxicity, particularly with three variant alleles: position 481C>T, position 590G>A, and position 857G>A [52,108].
Excess AcHZ is diverted into an alternate CYP pathway, resulting in the development of hepatotoxic metabolites. Data that show a higher risk of hepatitis when INH is combined with rifampin and other CYP inducers support this theory [98]. In one study, for example, N-acetyltransferase (NAT2) and CYP2E1 testing was performed in 89 patients receiving INH for treatment of latent tuberculosis [88]. NAT2 testing was not predictive of hepatotoxicity. However, the CYP2E1 *1a/*1a genotype (not CYP2E1 overall) significantly correlated with the development of elevated liver enzymes. Other data suggest that individuals carrying the CYP2E1 c1/c1 genotype are at greater risk for hepatotoxicity [101]. In a Chinese population, this genotype carried up to a 3.9-fold increased probability of hepatotoxicity in rapid acetylators and a 7.4-fold increased probability of hepatotoxicity in slow acetylators [101]. INH may also promote the development of hepatitis by inhibiting CYP2E and CYP2C, which could increase levels of other hepatotoxic drugs that are metabolized by these enzymes (eg, phenytoin and carbamazepine) [3].
Rifampin is seldom hepatotoxic when used alone but increases the activity of the CYP system and thereby can increase the production of toxic metabolites from INH. Toxic hepatitis is seen with the combination of INH and rifampin more frequently (5 to 8 percent) than with either drug alone [97,109-111], and hepatitis occurs sooner, mainly during the first month [111]. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Toxic hepatitis (The Basics)")
SUMMARY
●Isoniazid (INH) is a synthetic antibiotic that is bactericidal against replicating Mycobacterium tuberculosis. INH has been associated with two syndromes of hepatotoxicity: mild INH hepatotoxicity and INH hepatitis. (See 'Introduction' above.)
●Mild INH hepatotoxicity refers to hepatic injury that is typically subclinical and evidenced only by mildly elevated serum aminotransferases (usually <100 international units/L). Most cases are self-limited; in general, INH therapy can be continued with careful monitoring. Typically, aminotransferase levels return to normal within several weeks after discontinuation of INH. (See 'Mild INH hepatotoxicity' above.)
●INH hepatitis is a more serious liver injury syndrome than mild INH hepatotoxicity; it is usually symptomatic and may be fatal. It is an idiosyncratic reaction that is not clearly related to dose or duration of therapy. Risk factors are many and include age, alcohol use, use of concomitant hepatotoxic drugs, and prior or concurrent liver disease. (See 'INH hepatitis' above and 'Prevalence and risk factors' above.)
●Clinical manifestations of INH hepatitis typically occur within the first two to three months after initiation of therapy but may occur later; they include fatigue, malaise, anorexia, and/or nausea, with or without vomiting. Approximately one-third of patients have generalized flu-like symptoms, and some have right upper quadrant pain. Jaundice is a presenting feature in approximately 10 percent of cases and manifests days to weeks after onset of the above symptoms. (See 'Clinical manifestations' above.)
●The diagnosis of INH hepatitis should be suspected in patients taking INH who develop fatigue, malaise, anorexia, nausea, and/or vomiting in association with elevated serum aminotransferases. The diagnosis is established clinically, based on clinical manifestations and exclusion of other causes; the diagnosis is supported by resolution of elevated aminotransferases within several weeks after discontinuation of therapy. (See 'Diagnosis' above.)
●Clinical evaluation of patients with suspected INH hepatitis should include clinical history regarding alcohol use and exposure to other potential hepatotoxins. Laboratory evaluation should include testing for viral hepatitis and autoimmune hepatitis. (See 'Differential diagnosis' above.)
●Management of INH hepatitis consists of timely discontinuation of INH and other potential hepatotoxins. In general, hepatitis attributed to antituberculous drugs should prompt discontinuation of all hepatotoxic drugs if the serum bilirubin is ≥3 mg/dL or serum transaminases are more than five times the upper limit of normal (algorithm 1). (See 'Management' above.)
●Use of INH should be limited to appropriate clinical circumstances, and patients should be educated about the signs and symptoms of hepatic toxicity. Issues related to clinical and laboratory monitoring for patients on INH are discussed separately. (See "Treatment of latent tuberculosis infection in nonpregnant adults with HIV infection", section on 'Monitoring and adherence' and "Antituberculous drugs: An overview", section on 'Clinical and laboratory monitoring'.)
1 : Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.
2 : Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children.
3 : An official ATS statement: hepatotoxicity of antituberculosis therapy.
4 : Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid.
5 : Acetylation rates and monthly liver function tests during one year of isoniazid preventive therapy.
6 : Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity.
7 : Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis.
8 : Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population.
9 : Pattern of adverse drug reactions experienced by tuberculosis patients in a tertiary care teaching hospital in Western Nepal.
10 : Adverse effects of tuberculosis treatment: experience at an outpatient clinic of a teaching hospital in the city of São Paulo, Brazil.
11 : Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.
12 : Fatal isoniazid-induced hepatitis. Its risk during chemoprophylaxis.
13 : Mechanism of isoniazid-induced hepatotoxicity: then and now.
14 : Isoniazid-associated hepatitis. Report of an outbreak.
15 : Pharmacokinetics of the toxic hydrazino metabolites formed from isoniazid in humans.
16 : Use of isoniazid for latent tuberculosis infection in a public health clinic.
17 : Severe isoniazid-associated liver injuries among persons being treated for latent tuberculosis infection - United States, 2004-2008.
18 : Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study.
19 : Benefit-risk considerations in preventive treatment for tuberculosis in elderly persons.
20 : Adverse drug reactions and outcome of elderly patients on antituberculosis chemotherapy with and without rifampicin.
21 : A retrospective evaluation of completion rates, total cost, and adverse effects for treatment of latent tuberculosis infection in a public health clinic in central massachusetts.
22 : Isoniazid-associated hepatitis in 114 patients.
23 : Predisposing factors in hepatitis induced by isoniazid-rifampin treatment of tuberculosis.
24 : Predisposing factors in hepatitis induced by isoniazid-rifampin treatment of tuberculosis.
25 : Clinical pharmacokinetics of the antituberculosis drugs.
26 : Drug-related acute and chronic hepatitis.
27 : Risk factors for isoniazid (NIH)-induced liver dysfunction.
28 : Kinetics of rifampicin and isoniazid administered alone and in combination to normal subjects and patients with liver disease.
29 : Isoniazid-associated hepatitis deaths: a review of available information.
30 : Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus.
31 : Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement.
32 : Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement.
33 : The effect of ageing on isoniazid pharmacokinetics and hepatotoxicity in Fischer 344 rats.
34 : Estimated Impact of World Health Organization Latent Tuberculosis Screening Guidelines in a Region With a Low Tuberculosis Incidence: Retrospective Cohort Study.
35 : Adverse events in adults with latent tuberculosis infection receiving daily rifampicin or isoniazid: post-hoc safety analysis of two randomised controlled trials.
36 : Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study.
37 : Hepatotoxicity of pyrazinamide: cohort and case-control analyses.
38 : Deleterious influence of pyrazinamide on the outcome of patients with fulminant or subfulminant liver failure during antituberculous treatment including isoniazid.
39 : Hepatotoxicity of antitubercular treatments. Rationale for monitoring liver status.
40 : Challenges in reintroducing tuberculosis medications after hepatotoxicity.
41 : Isoniazid hepatotoxicity among drug users: the role of hepatitis C.
42 : Prevalence and interaction of hepatitis B and latent tuberculosis in Vietnamese immigrants to the United States.
43 : Risk factors for hepatotoxicity during anti-tuberculosis chemotherapy in Asian populations.
44 : The role of chronic hepatitis in isoniazid hepatotoxicity during treatment for latent tuberculosis infection.
45 : The safety of isoniazid tuberculosis preventive treatment in pregnant and postpartum women: systematic review and meta-analysis.
46 : Isoniazid-rifampin-induced hepatitis in hepatitis B carriers.
47 : Hepatotoxicity due to first-line anti-tuberculosis drugs: a five-year experience in a Taiwan medical centre.
48 : Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydranize metabolites.
49 : Role of polymorphic N-acetyl transferase2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis.
50 : The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.
51 : Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers.
52 : Pharmacogenetic association between NAT2 gene polymorphisms and isoniazid induced hepatotoxicity: trial sequence meta-analysis as evidence.
53 : The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid.
54 : Prevention of isoniazid toxicity by NAT2 genotyping in Senegalese tuberculosis patients.
55 : A Systematic Review and Meta-analysis of Isoniazid Pharmacokinetics in Healthy Volunteers and Patients with Tuberculosis.
56 : A pilot study to investigate the utility of NAT2 genotype-guided isoniazid monotherapy regimens in NAT2 slow acetylators.
57 : A pilot study to investigate the utility of NAT2 genotype-guided isoniazid monotherapy regimens in NAT2 slow acetylators.
58 : Hepatotoxicity During Isoniazid Preventive Therapy and Antiretroviral Therapy in People Living With HIV With Severe Immunosuppression: A Secondary Analysis of a Multi-Country Open-Label Randomized Controlled Clinical Trial.
59 : Isoniazid hepatitis.
60 : Hepatotoxicity of antimicrobial, antifungal, and antiparasitic agents.
61 : Treatment of hepatic failure secondary to isoniazid hepatitis with liver transplantation.
62 : Perspective: preventive isoniazid therapy and the liver.
63 : A new cocrystal of isoniazid-quercetin with hepatoprotective effect: The design, structure, and in vitro/in vivo performance evaluation.
64 : New hydrazides derivatives of isoniazid against Mycobacterium tuberculosis: Higher potency and lower hepatocytotoxicity.
65 : New isoniazid derivatives with improved pharmaco-toxicological profile: Obtaining, characterization and biological evaluation.
66 : Identification of Anti-tuberculosis Compounds From Aurone Analogs.
67 : The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide.
68 : The effect of isoniazid on transaminase levels.
69 : Isoniazid-related fatal hepatitis.
70 : Isoniazid prophylaxis and deaths in Baltimore, Maryland 1972.
71 : U.S. Public Health Service Cooperative trial of three rifampin-isoniazid regimens in treatment of pulmonary tuberculosis.
72 : Isoniazid metabolism and hepatotoxicity.
73 : Direct oxidation and covalent binding of isoniazid to rodent liver and human hepatic microsomes: humans are more like mice than rats.
74 : Mitochondrial oxidative stress and permeability transition in isoniazid and rifampicin induced liver injury in mice.
75 : Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure.
76 : A novel metabolite of antituberculosis therapy demonstrates host activation of isoniazid and formation of the isoniazid-NAD+ adduct.
77 : Clinical pharmacokinetics of isoniazid.
78 : Food significantly reduces plasma concentrations of first-line anti-tuberculosis drugs.
79 : Isoniazid: metabolic aspects and toxicological correlates.
80 : Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress.
81 : Isoniazid and iproniazid: activation of metabolites to toxic intermediates in man and rat.
82 : Role of hydrazine in the mechanism of isoniazid hepatotoxicity in rabbits.
83 : Isoniazid hepatoxicity: the relationship between covalent binding and metabolism in vivo.
84 : Monoacetylhydrazine as a metabolite of isoniazid in man.
85 : Determination of isonicotinic acid in the presence of isoniazid and acetylisoniazid. Studies on isonicotinic acid formation from isoniazid in isolated rat hepatocytes.
86 : Role of cytochrome P450 in hydrazine toxicity in isolated hepatocytes in vitro.
87 : Inhibition of isoniazid-induced hepatotoxicity in rabbits by pretreatment with an amidase inhibitor.
88 : CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis.
89 : Trimodality of isoniazid elimination: phenotype and genotype in patients with tuberculosis.
90 : Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms.
91 : A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis Chemotherapy.
92 : Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery.
93 : Genetic polymorphism in N-Acetyltransferase (NAT): Population distribution of NAT1 and NAT2 activity.
94 : Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients.
95 : The influence of human N-acetyltransferase genotype on the early bactericidal activity of isoniazid.
96 : The hepatic toxicity of isoniazid among rapid and slow acetylators of the drug.
97 : Acute and chronic drug-induced hepatitis.
98 : Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype.
99 : Lack of relationship between hepatic toxicity and acetylator phenotype in three thousand South Indian patients during treatment with isoniazid for tuberculosis.
100 : Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis.
101 : Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis.
102 : [Clinical relevance of N-acetyltransferase type 2 (NAT2) genetic polymorphism].
103 : Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury.
104 : Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis.
105 : Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury.
106 : N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group.
107 : Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients.
108 : Functional characterization of human N-acetyltransferase 2 (NAT2) single nucleotide polymorphisms.
109 : Toxic hepatitis with isoniazid and rifampin. A meta-analysis.
110 : Toxicity form rifampicin plus isoniazid and rifampicin plus ethambutol therapy.
111 : Données nouvelles sur les hépitites observées au cours des traitements antituberculeux incluant la rifampicine