结核分枝杆菌的 KatG 细菌过氧化氢酶-过氧化物酶是激活前药异烟肼 (INH) 所必需的 [1]。当 KatG 将异烟酰与 NADH 结合时，会产生异烟酰-NADH 复合物。该复合物可抑制天然烯烃聚酰亚胺-AcpM 底物和植物制造的酶，该复合物与基于烯烃聚酰亚胺的载体化妆品还原酶（称为 InhA）牢固结合。在此过程中，分枝杆菌培养基的细胞壁必须回流。一氧化氮是异烟肼被 KatG 激活时产生的序列之一，也被证明对另一种抗分枝杆菌前药 PA-824 的活性至关重要 [2] [3]。对于分裂速度快的分枝杆菌，异烟肼有杀菌作用；对于生长缓慢的分枝杆菌，具有抑菌作用[4]。

Absorption, Distribution and Excretion
Isoniazid is readily absorbed after oral administration; however, it may undergo significant first-pass metabolism. Co-administration with food reduces its absorption and bioavailability. Within 24 hours, 50% to 70% of the isoniazid dose is excreted in the urine. Isoniazid readily diffuses into all body fluids and cells. Significant concentrations of the drug can be detected in pleural fluid and ascites; concentrations in cerebrospinal fluid are similar to those in plasma. Isoniazid penetrates caseous material well. Initial drug concentrations in plasma and muscle are higher than in infected tissue, but the latter maintains drug concentrations for a prolonged period, well above the concentrations required for bacteriostasis. 75% to 95% of the isoniazid dose is excreted in the urine within 24 hours, primarily as metabolites.
Widely distributed in all body fluids and tissues, including cerebrospinal fluid, pleural fluid and ascites, skin, sputum, saliva, lungs, muscle and caseous tissue. Isoniazid can be excreted through the placenta and secreted into breast milk.
For more complete data on the absorption, distribution and excretion of isoniazids (10 in total), please visit the HSDB record page.

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Metabolism/Metabolites
Primarily metabolized in the liver. Isoniazid is acetylated to N-acetylisoniazid by N-acetyltransferases; it is then bioconverted to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine is N-hydroxylated by the cytochrome P450 mixed oxidase system to form an active intermediate metabolite, which leads to hepatotoxicity. The acetylation rate is genetically determined. Slow acetylaters are characterized by a relative deficiency of hepatic N-acetyltransferases.
Isoniazid is mainly inactivated in the liver through acetylation and deacetylation. The metabolites of this drug include acetylisoniazid, isonicotinic acid, monoacetylhydrazine, diacetylhydrazine, and isonicoylglycine. In humans, the most important metabolic products of isoniazid in urine are 1-acetyl-2-isonicotinamide (acetylisoniazid), N-acetyl-N'-isonicotinic acid, isonicotinylglycine, isonicotinylhydrazone pyruvate, and α-ketoglutarate isonicotinylhydrazone. In rabbits, the metabolic products of isoniazid are isonicotinic acid and ammonia, with ammonia arising from the rapid breakdown of the hydrazine group. The acetylation of acetylisoniazid produces monoacetylhydrazine, which has been shown to be a potent hepatotoxin in animals. The microsomal metabolism of monoacetylhydrazine in animals produces an active acylated substance that can covalently bind to tissue macromolecules (such as hepatoproteins), leading to hepatocyte necrosis. For more complete data on the metabolism/metabolites of isoniazid (a total of 6 metabolites), please visit the HSDB record page. Known metabolites of isoniazid include 3,4,5-trihydroxy-6-[2-(pyridin-4-carbonyl)hydrazino]oxacyclohexane-2-carboxylic acid and N-acetylononiazid. It is primarily metabolized in the liver. Isoniazid is acetylated by N-acetyltransferases to N-acetylononiazid; isoniazid is then bioconverted to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine, under N-hydroxylation by the cytochrome P450 mixed oxidase system, forms an active intermediate metabolite that leads to hepatotoxicity. The acetylation rate is genetically determined. Slow acetylaters are characterized by a relative deficiency of hepatic N-acetyltransferases. Elimination pathway: 50% to 70% of the isoniazid dose is excreted in the urine within 24 hours. Half-life: Fast acetylaters: 0.5 to 1.6 hours. Slow acetylaters: 2 to 5 hours.

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Biological half-life
Fast acetylaters: 0.5 to 1.6 hours.
Slow acetylation: 2 to 5 hours.
Adults (including elderly patients) - Rapid acetylation: 0.5 to 1.6 hours. Slow acetylation: 2 to 5 hours. Acute and chronic liver disease: Half-life may be prolonged (6.7 hours, compared to 3.2 hours in the control group).
Children (1.5 to 15 years) - 2.3 to 4.9 hours.
Neonatals - 7.8 hours; the half-life for neonates given isoniazid transplacently is 19.8 hours. The long half-life may be due to the limited acetylation capacity of neonates.

Hepatotoxicity
Despite its limited use, isoniazid remains one of the most common causes of severe, specific liver injury in the United States. Isoniazid treatment results in transient elevations of serum transaminases in 10% to 20% of patients, with 3% to 5% experiencing transaminase levels exceeding five times the upper limit of normal (ULN). These elevations are often asymptomatic and frequently resolve spontaneously without dose adjustment (Case 1 and 2). Furthermore, isoniazid can cause clinically apparent acute liver injury with jaundice in 0.5% to 1% of patients, with a mortality rate of 0.05% to 0.1%. The incidence of liver injury varies considerably in published literature. Age is likely a major contributing factor to this variation. The estimated incidence of clinically overt hepatitis caused by isoniazid is 0.5% in patients aged 20 to 35 years, 1.5% in patients aged 35 to 50 years, and 3% or higher in those over 50 years of age. Isoniazid hepatotoxicity is rare in children (but it does occur and can be fatal). Other risk factors include a history of liver disease (hepatitis B or C), concurrent use of rifampin or pyrazinamide, and possible alcoholism, Black race, and genetic factors. The typical onset time for injury is 2 weeks to 6 months, but can be as long as 1 year and as short as 1 week. The onset is usually insidious, similar to acute viral hepatitis, with prodromal symptoms including nausea, anorexia, abdominal discomfort, and fatigue, followed by darkening of urine and jaundice (cases 3 and 4). The pattern of elevated liver enzymes is usually hepatocellular, with significantly elevated ALT levels (>10 times the upper limit of normal) and slightly elevated alkaline phosphatase levels (usually
Probability score: A (established clinically significant cause of liver injury).
Pregnancy and lactation effects
◉ Overview of medication use during lactation
Because isoniazid is present in low amounts in breast milk and can be safely administered directly to infants, adverse reactions in infants are unlikely, but infants should be monitored for rare jaundice. Giving the mother a once-daily dose before the infant's longest sleep period can reduce the infant's intake. The amount of isoniazid in breast milk is insufficient to treat tuberculosis in breastfed infants. If a breastfed infant is treated with isoniazid, pyridoxine should also be administered daily. mg/kg. The US Centers for Disease Control and Prevention and other professional agencies point out that women taking isoniazid should not be discouraged from breastfeeding. All breastfeeding mothers taking isoniazid should take 25 mg of pyridoxine orally daily. A study of breastfeeding mothers in Africa co-infected with HIV and tuberculosis found that mothers taking isoniazid had an increased risk of niacin deficiency (pellagra). The authors suggest that multivitamin supplementation may be beneficial during isoniazid treatment in malnourished populations. ◉ Effects on Breastfed Infants
In a non-controlled study, researchers measured 6β-hydroxycorticosteroid (6β-CCR) levels in 10 male infants whose mothers had tuberculosis and were taking 1 gram of ethambutol and 300 mg of isoniazid daily. Simultaneously, researchers also measured 6β-CCR levels in infants born to mothers of 10 male infants (who apparently did not have tuberculosis) who were not receiving any long-term medication. The results showed that infants born to mothers taking anti-tuberculosis drugs consistently had lower 6β-CCR levels than infants born to mothers taking anti-tuberculosis drugs in all eight measurements. From 9 days after birth... From day 0 to day 195, measurements were taken every 15 days, but these differences were only statistically significant at day 120 and day 195. The authors attributed the lower cortisol levels to the anti-tuberculosis drugs in breast milk inhibiting the liver's metabolism of cortisol to 6β-hydroxycortisol. However, ethambutol is known not to inhibit drug metabolism, so if this effect occurred, it was more likely caused by isoniazid. A woman took rifampin 450 mg, isoniazid 300 mg, and ethambutol 1200 mg daily during pregnancy and rifampin 450 mg and isoniazid 300 mg daily for the first 7 months of lactation. (Dosage not specified). The infant had mildly elevated serum liver enzymes at birth, which persisted for 1 to 2 years (alanine aminotransferase) but no other adverse reactions occurred. Isoniazid was used as part of… Two pregnant women received multidrug combination therapy for multidrug-resistant tuberculosis during the mid-to-late stages of pregnancy and postpartum. Both of their infants were breastfed (the extent and duration of breastfeeding were not specified). The two children were developing normally at 3.9 and 4.6 years of age, respectively, with one child having mild language delay. Two mothers in Turkey were at 30 weeks and 3… They were diagnosed with tuberculosis at 4 weeks of age. They immediately began taking isoniazid 300 mg, rifampin 600 mg, and pyridoxine 50 mg once daily for 6 months; simultaneously, they received pyrazinamide 25 mg/kg and ethambutol 25 mg/kg once daily for 2 months. Both mothers breastfed (feeding extent not specified). Their infants received isoniazid 5 mg/kg once daily for 3 months as prophylactic treatment. After 3 months, the tuberculin skin test was negative, and both infants were tuberculosis-free by 1 year of age. Age. No adverse drug reactions were mentioned.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
Very low (0-10%)

[1]. An oxyferrous heme/protein-based radical intermediate is catalytically competent in the catalase reaction of Mycobacterium tuberculosis catalase-peroxidase (KatG). J Biol Chem, 2009. 284(11): p. 7017-29.

[2]. Nitric oxide generated from isoniazid activation by KatG: source of nitric oxide and activity against Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2004. 48(8): p. 3006-9.

[3]. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science, 2008. 322(5906): p. 1392-5.

[4]. Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the guinea pig. J Infect Dis, 2009. 200(7): p. 1136-43.

Isoniazid is an odorless, colorless or white crystalline powder. It tastes slightly sweet initially, then bitter. A 1% aqueous solution has a pH of 5.5-6.5, and a 5% aqueous solution has a pH of 6-8. (NTP, 1992)
Isoniazid is a carboxylic acid hydrazine, formed by the condensation of pyridine-4-carboxylic acid and hydrazine. It is an anti-tuberculosis drug and also a drug allergen. Its structure is similar to isoniazid.
Isoniazid is a prescription antibiotic approved by the U.S. Food and Drug Administration (FDA) for the prevention and treatment of tuberculosis (TB).
TB can be an opportunistic infection (OI) of HIV infection.
It is primarily used as an anti-tuberculosis drug. Isoniazid remains the first-line treatment for TB.
Isoniazid is an anti-mycobacterial drug.
Isoniazid is the most reliable and commonly used drug for treating tuberculosis. Isoniazid treatment typically results in a mild, transient, and asymptomatic increase in serum transaminase levels. More importantly, isoniazid is a known cause of acute liver injury, which can be severe and sometimes fatal. Isoniazid has been reported to infect Acriflavin ochraceus, Ganoderma lucidum, and several other microorganisms with relevant data. Isoniazid is a synthetic derivative of nicotinic acid and possesses anti-mycobacterial activity. Although its mechanism of action is not fully understood, isoniazid appears to block the synthesis of mycolic acid, a major component of the mycobacterial cell wall. The drug is only effective against actively growing mycobacteria because it is a prodrug and requires activation in susceptible mycobacteria to exert its effect. Isoniazid also interferes with the metabolism of vitamin B6 by mycobacteria. Resistance develops due to decreased bacterial cell wall penetration. (NCI04) Primarily used as an antimicrobial agent to suppress tuberculosis. It remains the drug of choice for treating tuberculosis. Primarily used as an antimicrobial agent to suppress tuberculosis. It remains the drug of choice for treating tuberculosis. See also: Isoniazid; Rifampin (component); Stevia leaf (part); Isoniazid; Pyrazinamide; Rifampin (component).

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Drug Indications
Isoniazid is used to treat all tuberculosis cases sensitive to isoniazid. It can also be used in combination with rifampin and pyrazinamide.
For active immunization of 1-day-old chicks to reduce clinical symptoms (diarrhea), intestinal lesions, and oocyst expulsion associated with coccidiosis caused by Eimeria tenella, Eimeria brucellae, Eimeria giant, Eimeria necrotic, and Eimeria tenella.

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Mechanism of Action
Isoniazid is a prodrug that must be activated by bacterial catalase. Specifically, the activation process involves hydrazine reducing the iron KatG catalase-peroxidase of mycobacteria and reacting with oxygen to form an oxyferrous enzyme complex. After activation, isoniazid inhibits the synthesis of mycolic acid, an important component of the mycobacterial cell wall. Isoniazid exhibits bactericidal activity against actively growing intracellular and extracellular Mycobacterium tuberculosis at therapeutic concentrations. Specifically, isoniazid inhibits the enoyl reductase InhA of Mycobacterium tuberculosis by forming a covalent adduct with the NAD cofactor. This INH-NAD adduct acts as a slow, tight competitive inhibitor of InhA. Although the mechanism of action of isoniazid is not fully understood, several hypotheses have been proposed. These hypotheses include its effects on lipid, nucleic acid biosynthesis, and glycolysis. …It is thought that the primary action of isoniazid is to inhibit the biosynthesis of mycolic acid, an important component of the mycobacterial cell wall. Since mycolic acid is specific to mycobacteria, this action could explain the high selectivity of isoniazid's antibacterial activity. Isoniazid leads to a loss of acid resistance and a decrease in the content of methanol-extractable lipids in microorganisms. Isoniazid has an inhibitory effect on dormant Mycobacterium tuberculosis but a bactericidal effect on rapidly dividing microorganisms. Its minimum inhibitory concentration (MIC) for tuberculosis is 0.025 to 0.05 μg/mL.

C6H7N3O

137.1393

137.058

54-85-3

Isoniazid-d4;774596-24-6

3767

White to off-white solid powder

1.2±0.1 g/cm3

171-173 °C(lit.)

>250°C

1.584

-0.89

68.01

2

3

1

10

120

0

QRXWMOHMRWLFEY-UHFFFAOYSA-N

InChI=1S/C6H7N3O/c7-9-6(10)5-1-3-8-4-2-5/h1-4H,7H2,(H,9,10)

pyridine-4-carbohydrazide

Isoniazid HyzydIsovitIsonicotinylhydrazideNydrazidHydra

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 本产品在运输和储存过程中需避光。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~364.59 mM)
H2O : ~33.33 mg/mL (~243.04 mM)

配方 1 中的溶解度: 150 mg/mL (1093.77 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。