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Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

log Kow= -0.60

-1

-0.5

Crystals

Crystals from water or alcohol

Crystals from water or ethyl alcohol

Soluble (NTP, 1992)

Solubility (mg/ml, 25 °C): methanol 13.8; absolute ethanol 5.7; isopropanol 3.8; ether 1.0; isooctane 0.01; chloroform 7.4

In water, 15 mg/ml @ 25 °C

9.37e+01 g/L

>18.5 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Anti-infective Agents; Antitubercular Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Antituberculosis medicines

376 to 379 °F (NTP, 1992)

192 °C

192 °C

Pyrazinamide is a white powder. Sublimes from 318 °F. (NTP, 1992)

Solid

This chemical does not meet GHS hazard criteria for 7.1% (4 of 56) of reports.

Danger

H310 (92.9%): Fatal in contact with skin [Danger Acute toxicity, dermal]

P260, P262, P264, P270, P271, P280, P284, P302+P352, P304+P340, P316, P320, P321, P332+P317, P361+P364, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 56 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

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.

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.

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.

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)

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.

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.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=98-96-4]

/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

TR-048: Bioassay of Pyrazinamide for Possible Carcinogenicity (CASRN 98-96-4) (1978 )

01/18/78

No Evidence

No Evidence

No Evidence

Drug Induced Liver Injury Rank (DILIrank 2.0)

Pyrazinamide

vLess-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ Moderately toxic by ingestion, subcutaneous, and intraperitoneal routes.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Pyrazinamide reportedly was not carcinogenic in rats or male mice (as determined in lifetime bioassays) when administered in daily doses of approximately 10-40 times the maximum recommended human dose; results in female mice could not be determined because of insufficient numbers of surviving mice in the control group.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ We have tested Pyrazinamide (PZA), an essential component of modern short-course tuberculosis treatment regimen, for teratogenicity using Wistar rats. The drug was given by oral intubation from 6-15 days of gestation, at doses of 0, 25, 100 and 500 mg/kg body weight per day. Reduction in body weight and food consumption were observed in the treated dams. On day 20 of gestation, all the dams were killed by cervical dislocation and signs of maternal toxicity, reproductive indices and fetal measurements were recorded. Dams given doses of 100 and 500 mg/kg had significantly higher incidence of reabsorbed fetuses, reduced litter size, and impaired neonatal growth than those given no PZA or only 25 mg/kg dose. External visceral and skeletal examination of all fetuses of PZA-treated dams showed several types of variations which were neither dose related nor having a consistent pattern. However, these variations occurred mostly in the dams treated with the dose of 500 mg/kg. In conclusion, these data show that in Wistar rats, only high doses of PZA (100 and 500 mg/kg) produced fetotoxicity. No evidence of teratogenic effect of the drug was observed.

/GENOTOXICITY/ Pyrazinamide ...did induce chromosomal aberrations in human lymphocyte cell cultures.

For more Non-Human Toxicity Excerpts (Complete) data for PYRAZINAMIDE (7 total), please visit the HSDB record page.

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.

LDLo Rat oral 3 g/kg

LDLo Mouse oral 3 g/kg

LD50 Mouse intraperitoneal 1680 mg/kg

LD50 Mouse subcutaneous 2793 mg/kg

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.

J04AK01

J - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

J04AK01

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 <i>Mycobacterium tuberculosis</i>. 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.

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.

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.

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).

2KNI5N06TI

PYRAZINAMIDE

Established Pharmacologic Class [EPC] - Antimycobacterial

Pyrazinamide is an Antimycobacterial.

PYRAZINAMIDE

Antimycobacterial [EPC]

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.

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.

Antibacterial (tuberculostatic)

Pyrazinamide is a bactericidal antitubercular agent that is used in combination with other antitubercular agents, especially in developing nations. ... In the US, pyrazinamide is generally reserved for combination use in patients infected with drug-resistant strains.

Use (kg; approx.) in Germany (2009): >750

Quinoxaline + ammonia (side-chain oxidation/decarboxylation/amide formation)

Prepd by ammonolysis of methyl pyrazinoate (from quinoxaline): Dalmer, Walter, Ger. Pat. 632,257 (1936 to E. Merck); Brit. Pat. 451,304; U.S. pat. 2,149,279 (1939 to Merck & Co.); Hall, Spoerri, J. Am. Chem. Soc. 62, 664 (1940); Williams, Kushner, U.S. pat. 2,677,641 (1954 to Am Cyanamid); by thermal decarboxylation of pyrazine-2-carboxamide-3-carboxylic acid: Webb, Arlt, U.S. pat. 2,780,624 (1957 to Am. Cyanamid).

Prepn: O. Dalmer, E. Walter, DE 632257 (1936 to E. Merck); eidem, US 2149279 (1939 to Merck & Co.)

The rifampicin-pyrazinamide combination is known as Rifater (Merrell Dow).

Pyrazinamide is commercially available alone and in fixed combination with isoniazid and rifampin.