Pyrazinamide

123.11

123.11

202-717-6

2KNI5N06TI

757304|14911

DTXSID9021215

C29395

Crystals|Crystals from water or alcohol|Crystals from water or ethyl alcohol

J04AK01|J - Antiinfectives for systemic use

2934999090

68.9

-0.6

White Crystalline Powder or Needles

1.4475 g/cm³

192 °C

SUB (NTP, 1992)

>110°(230°F)

1.648

H2O: soluble 50mg/mL

-20°C Freezer

LD50 intraperitoneal in mouse: 1680mg/kg

Aqueous solutions are neutral

-0.5None

pKa= 0.5

122.8 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Begins to sublime at 60 °C

Water soluble.

Amides and Imides

PYRAZINAMIDE is an amide derivative. Incompatible with strong acids and bases, and especially incompatible with strong reducing agents such as hydrides. May react with active metals or nitrides to produce flammable gaseous hydrogen. Incompatible with strongly oxidizing acids, peroxides, and hydroperoxides.

NONH for all modes of transport

3

11-34

22-24/25-45-36/37/39-26-16

UQ2275000

F,C

P260, P262, P264, P270, P271, P280, P284, P302+P350, P302+P352, P304+P340, P310, P320, P321, P322, P332+P313, P361, P362, P363, P403+P233, P405, P501

H310

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl pyrazinamide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H310 (100%): Fatal in contact with skin [Danger Acute toxicity, dermal]|P260, P262, P264, P270, P271, P280, P284, P302+P350, P302+P352, P304+P340, P310, P320, P321, P322, P332+P313, P361, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 55 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Side effects include liver injury, arthralgias, anorexia, nausea and vomiting, dysuria,malaise and fever, sideroblastic anemia, adverse effects on the blood clotting mechanism or vascular integrity, and hypersensitivity reactions such as urticaria, pruritis and skin rashes.

Combination therapy for tuberculosis using pyrazinamide is commonly associated with transient and asymptomatic elevations in the serum aminotransferase levels. These elevations are usually less than five times the upper limit of the normal range. Because pyrazinamide is used only in combination with other antituberculosis medications, its contributions to serum enzyme elevations is not completely clear, but it is frequently incriminated in transient serum enzyme elevations. Clinically apparent liver disease with symptoms and jaundice also occur with pyrazinamide therapy and it is often considered the culprit in causing liver injury in the face of double or triple antituberculosis therapy (Case 1). Indeed, the use of a short, 2 month course of combination therapy with rifampin and pyrazinamide for latent tuberculosis was abandoned because of the frequency of severe liver injury with this regimen that was occasionally fatal (Case 2). The onset of injury due to pyrazinamide is generally after 4 to 8 weeks and occasionally becomes apparent only after the pyrazinamide is stopped. The pattern of liver enzyme elevations is typically hepatocellular and the clinical syndrome resembles acute viral hepatitis, much like isoniazid hepatotoxicity. Features of hypersensitivity (rash, fever and eosinophilia) are uncommon as are autoantibody formation. Liver biopsy demonstrates changes typical of acute hepatitis with portal and lobular inflammation, hepatocellular necrosis and variable degrees of cholestasis.

Pyrazinamide may increase serum uric acid concentrations and decrease the efficacy of gout therapy; dosage adjustments of these medications /allopurinol, colchicine, probenecid, sulfinpyrazone/ may be necessary to control hyperuricemia and gout when antigout medications are used concurrently with pyrazinamide.|Concurrent use with pyrazinamide may decrease the serum concentrations of cyclosporine, possibly leading to inadequate immunosuppression; cyclosporine serum concentrations should be monitored.|A 35 year old black Somalian woman with miliary tuberculosis developed hepatotoxicity after a few days of treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol. After withdrawal of all drugs the liver profile returned to normal and remained so after challenge with isoniazid. Hepatotoxicity recurred when rifampicin was added, but it was well tolerated when reintroduced without isoniazid.|The utility of pyrazinamide (PZA) in the short-course antituberculous treatment is well established. All available data support the idea that the PZA metabolite pyrazinoic acid (PA) is the active compound against M. tuberculosis. This situation warranted a deeper investigation of possible interactions with respect to its metabolic disposition. Caffeine, which is widely used as a drug and is a common constituent of most diets, shares with PZA the same metabolic enzyme, xanthine oxidase (XO). This study investigated if, and in what manner, concomitant administration of caffeine affects PZA metabolism. PZA and caffeine, in various doses (PZA=50 or 100 mg kg(-1) and caffeine= 0, 50, 100, and 150 mg kg(-1)), were administered to female Sprague-Dawley rats. PZA and its three main metabolites were quantified in 24 h urine samples by reversed phase-HPLC Concomitant administration of 100 mg kg(-1) caffeine and 50 mg kg(-1) PZA increased from the excretion (p<0.05) of the most water-soluble and the least toxic PZA metabolite 5-hydroxypyrazinoic acid (5-OH-PA) from 66.18+/-10.87 to 94.56+/-8.65 micromol/24 h. This effect was more pronounced when 100 mg kg(-1) of PZA was administered increasing excretion of 5-OH-PA from 113.28+/-70 to 173.23+/-17.82 micromol/24 h. These results show that the metabolic disposition of PZA is affected by concomitant caffeine intake.|For more Interactions (Complete) data for PYRAZINAMIDE (9 total), please visit the HSDB record page.

LDLo Rat oral 3 g/kg|LDLo Mouse oral 3 g/kg|LD50 Mouse intraperitoneal 1680 mg/kg|LD50 Mouse subcutaneous 2793 mg/kg

A bioassay of the tuberculostatic drug pyrazinamide for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered pyrazinamide at one of two doses, either 5,000 or 10,000 ppm, for 78 weeks, and then observed for an additional 26 or 27 weeks. Matched controls consisted of groups of 15 untreated rats and 15 untreated mice of each sex. High-dose male mice died or were killed by week 92; all other surviving animals were killed at weeks 104 or 105. Mean body weights of the dosed male rats were slightly lower than those of the matched controls, while mean body weights of the dosed females were more nearly comparable to those of the controls. A sufficient number of rats in each group was at risk to termination of the study at weeks 104-105 for the development of late-appearing tumors. In mice, administration of pyrazinamide had no consistent effect on mean body weights. Survival to termination of the study was low, particularly among the control groups. In rats, no lesions could clearly be related to administration of the chemical. In mice, interstitial and suppurative myocarditis in the dosed animals and suppurative bronchopneumonias in both dosed and matched control mice of each sex were associated with increased deaths. In the females, there was a significant positive dose-related trend (P=0.037) in the incidence of lymphoma (matched controls 0/13, low-dose 2/25, high-dose 6/29); however, the incidences in each of the dosed groups were not significant when compared with that in the matched controls. In addition, the poor survival and the small size of the control group precluded making a clear association of the incidence of these tumors with administration of the chemical. It is concluded that under the conditions of this bioassay, the early deaths and small size of the control group precluded a conclusion regarding the carcinogenicity of pyrazinamide in female B6C3F1 mice. Pyrazinamide was not carcinogenic for Fischer 344 rats or for male mice.

~10% (bound to plasma proteins)

For the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents.

Pyrazinamide is a first line antituberculosis medication, but is used only in combination with other antituberculosis medications such as isoniazid or rifampin. Pyrazinamide is associated with transient and asymptomatic elevations in serum aminotransferase levels and is a well known cause of clinically apparent, acute liver injury that can be severe and even fatal.

Antituberculosis Agents

Antitubercular Agents|Pyrazinamide is indicated in combination with other antimycobacterial drugs, in the treatment of tuberculosis. Pyrazinamide is effective only against mycobacteria. /Included in US product labeling/|Rifampin, isoniazid, and pyrazinamide combination is indicated in the initial phase of the short-course treatment of all forms of tuberculosis. During this phase, which should last 2 months, rifampin, isoniazid, and pyrazinamide combination should be administered on a daily, continuous basis. Additional medications are indicated if multidrug-resistant tuberculosis is suspected. /Included in US product labeling/|Pyrazinamide has become an important component of short-term (6 month) multiple-drug therapy of tuberculosis.

Patients hypersensitive to ethionamide, isoniazid, niacin (nicotinic acid), or other chemically related medications may be hypersensitive to this medication also.|Pyrazinamide should be used only when close observation of the patient is possible. Serum AST (SGOT), ALT (SGPT), and uric acid concentrations should be determined prior to and every 2-4 weeks during pyrazinamide therapy. If signs of hepatic damage occur, pyrazinamide should be discontinued.|Hepatotoxicity is the most commonly reported adverse effect, with elevated transaminase levels being the earliest indication of toxicity...Pyrazinamide decreases the tubular excretion of uric acid, which may induce an acute gouty arthritis. Other adverse reactions include nausea, vomiting, dysuria, malaise, fever and skin rashes.|The drug inhibits excretion of urate, resulting in hyperuricemia in nearly all patients; acute episodes of gout have occurred. Other untoward effects that have been observed with pyrazinamide are arthralgias, anorexia, nausea and vomiting, dysuria, malaise and fever.|For more Drug Warnings (Complete) data for PYRAZINAMIDE (19 total), please visit the HSDB record page.

Pyrazinamide kills or stops the growth of certain bacteria that cause tuberculosis (TB). It is used with other drugs to treat tuberculosis. It is a highly specific agent and is active only against Mycobacterium tuberculosis. In vitro and in vivo, the drug is active only at a slightly acid pH. Pyrazinamie gets activated to Pyrazinoic acid in the bacilli where it interferes with fatty acid synthase FAS I. This interferes with the bacteriums ability to synthesize new fatty acids, required for growth and replication.

Drugs used in the treatment of tuberculosis. They are divided into two main classes: "first-line" agents, those with the greatest efficacy and acceptable degrees of toxicity used successfully in the great majority of cases; and "second-line" drugs used in drug-resistant cases or those in which some other patient-related condition has compromised the effectiveness of primary therapy. (See all compounds classified as Antitubercular Agents.)

Rapidly and well absorbed from the gastrointestinal tract.|Approximately 70% of an oral dose is excreted in the urine, mainly by glomerular filtration within 24 hours|Pyrazinamide is well absorbed from the gastrointestinal tract, and it is widely distributed throughout the body. The oral administration of 500 mg produces plasma concentrations of about 9-12 ug/ml at two hours and 7 ug/ml at 8 hours.|Pyrazinamide is well absorbed from the GI tract. Following a single 500 mg oral dose in healthy adults, peak plasma concentrations of pyrazinamide ranging from 9-12 ug/ml are attained within 2 hours; plasma concentrations of the drug average 7 ug/ml at 8 hours and 2 ug/ml at 24 hours. Plasma concentrations following doses of 20-25 mg/kg reportedly range from 3-50 ug/ml. Plasma concentrations of pyrazinoic acid, the major active metabolite of pyrazinamide, generally are greater than those of the parent drug and peak within 4-8 hours after an oral dose of the drug.|In a single-dose study in healthy fasting males, the extent of absorption (as measured by area under the plasma concentration-time curve) of isoniazid, rifampin, or pyrazinamide in dosages of 250, 6O0, or 1500 mg, respectively, was similar whether the drugs were administered individually as capsules (rifampin) and tablets (isoniazid and pyrazinamide) or as a fixed combination containing isoniazid 50 mg, rifampin 120 mg, and pyrazinamide 300 mg per tablet.|Pyrazinamide is widely distributed into body tissues and fluids including the liver, lungs, and CSF. In a limited number of adults with tuberculous meningitis, mean serum and CSF concentrations of pyrazinamide 2 hours after an oral dose of approximately 41 mg/kg were 52 and 39 ug/ml, respectively. Within 5 hours after an oral dose, CSF concentrations of pyrazinamide are reported to be approximately equal to concurrent plasma concentrations of the drug. Plasma protein binding of pyrazinamide (determined by ultrafiltration) in a limited number of healthy men averaged approximately 17% at a pyrazinamide concentration of 20 ug/ml. It is not known if pyrazinamide crosses the placenta. It is not known if pyrazinamide is distributed into milk.|For more Absorption, Distribution and Excretion (Complete) data for PYRAZINAMIDE (12 total), please visit the HSDB record page.

Hepatic.|Pyrazinamide is hydrolyzed to pyrazinoic acid and subsequently hydroxylated to 5-hydroxypyrazinoic acid, the major excretory product.|The major metabolic pathway of pyrazinamide is conversion to pyrazinoic acid followed by subsequent conversion to hydroxypyrazinoic acid, a reaction catalyzed by xanthine oxidase.|Eight healthy volunteers were treated with a single dose of pyrazinamide 35 mg/kg. The aim of the study was to evaluate the pharmacokinetic profile of the product and of its metabolites. Urine and blood samples were collected till the 60th h. The kinetics of pyrazinamide could be characterized as follows: CPmax = 50.1 micrograms/ml, tmax less than 1 h, t1/2 alpha = 3.2 h, t1/2 beta = 23 h, U(0-60 h) = 1.6% of the dose administered. The kinetics of the main metabolite, the pyrazinoic acid, gave the following values: CPmax = 66.6 micrograms/ml, tmax = 4 h, t1/2 beta = 12.3 h, U(0-60 h) = 37.5%, of the administered dose.|All available data support the idea that the PZA metabolite pyrazinoic acid (PA) is the active compound against M. tuberculosis. ... Caffeine, which is widely used as a drug and is a common constituent of most diets, shares with PZA the same metabolic enzyme, xanthine oxidase (XO).

9-10 hours (normal conditions)|The plasma half-life is 9-10 hours in patients with normal renal function.|The half-life of pyrazinamide is 23 hours. ... The elimination half-life is 10 to 16 hours.|The plasma half-life of pyrazinamide is 9-10 hours in patients with normal renal and hepatic function. The plasma half-life of the drug may be prolonged in patients with impaired renal or hepatic function.

Pyrazinamide diffuses into active _M. tuberculosis_ that express pyrazinamidase enzyme that converts pyrazinamide to the active form pyrazinoic acid. Pyrazinoic acid can leak out under acidic conditions to be converted to the protonated conjugate acid, which is readily diffused back into the bacilli and accumulate intracellularly. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids. However, this theory was thought to have been discounted. However, further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids. This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I. It has also been suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Pyrazinoic acid has also been shown to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation. This may explain the ability of the drug to kill dormant mycobacteria.|Pyrazinamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of the infection and the susceptibility of the infecting organism. In vitro and in vivo, the drug is active only at a slightly acidic pH. The exact mechanism of action of pyrazinamide has not been fully elucidated. The antimycobacterial activity of pyrazinamide appears to partly depend on conversion of the drug to pyrazinoic acid. Susceptible strains of Mycobacterium tuberculosis produce pyrazinamidase, an enzyme that deaminates pyrazinamide to pyrazinoic acid, and the in vitro susceptibility of a given strain of the organism appears to correspond to its pyrazinamidase activity. In vitro studies indicate that pyrazinoic acid has specific antimycobacterial activity against Mycobacterium tuberculosis. In addition, the fact that pyrazinoic acid lowers the pH of the environment below that which is necessary for growth of Mycobacterium tuberculosis appears to contribute to the drug's antimycobacterial activity in vitro.|Unknown; pyrazinamide may be bacteriostatic or bactericidal, depending on its concentration and the susceptibility of the organism. It is active in vitro at an acidic pH of 5.6 or less, similar to that found in early, active tubercular inflammatory lesions.

SYMPTOMS: Athralgias, anorexia, nausea and vomiting, dysuria, malaise and fever. ACUTE/CHRONIC HAZARDS: Toxic. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. If symptoms (such as redness or irritation) develop, immediately transport the victim to a hospital. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

/SPECIAL STUDIES/ Cytogenetic analyses were carried out in lymphocytes of 15 untreated tuberculosis (tb) patients and 15 other tb patients who had received combined tuberculostatic chemotherapy HRZ (isoniazid + rifampicin + pyrazinamide) for 2 months. The frequency of chromosomal aberrations and sister chromatid exchanges (SCEs) did not show any statistically significant differences in the patients before treatment and after exposure to combined HRZ therapy as compared to controls (p > 0.051. However, /it was/ observed that the mitotic index was significantly decr in both groups (p < 0.05).

Pyrazinamide

The rifampicin-pyrazinamide combination is known as Rifater (Merrell Dow).|Pyrazinamide is commercially available alone and in fixed combination with isoniazid and rifampin.

2-Pyrazinecarboxamide: INACTIVE

Analyte: pyrazinamde; matrix: pharmaceutical preparation (tablet); procedure: liquid chromatography with detection at 270 nm and comparison to standards (assay purity)|Analyte: pyrazinamde; matrix: pharmaceutical preparation (tablet); procedure: chemical reaction with sodium hydroxide to generate odor of ammonia (chemical identification)|Analyte: pyrazinamde; matrix: pharmaceutical preparation (tablet); procedure: ultraviolet absorption spectrophotometry with comparison to standards (chemical identification)|Analyte: pyrazinamde; matrix: pharmaceutical preparation (tablet); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification)|For more Analytic Laboratory Methods (Complete) data for PYRAZINAMIDE (8 total), please visit the HSDB record page.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients