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PubMed2001

Pyrazinamide use as a method of estimating under-reporting of tuberculosis.

OBJECTIVE: To develop a method of validating the notification of active tuberculosis by physicians in the Netherlands. METHOD: The chemotherapeutic agent pyrazinamide was used as a marker for the occurrence of tuberculosis. On the basis of defined daily doses (DDD) of pyrazinamide dispensed to out-patients, an estimate was made of the number of patients with tuberculosis in the Netherlands in the period 1994-1998. DDD is a technical unit of measurement and does not necessarily reflect the recommended or actual dose used. Usually it is based on the average dosage per day for the main indication in adults with normal organ function. The Dutch Drug Information Project (GIP) of the Health Care Insurance Board (CVZ) provided the DDD data. Based on the notification of tuberculosis patients to the Netherlands Tuberculosis Register (NTR) we calculated how much pyrazinamide (measured in DDDs) these patients would have used depending on their body weight. RESULTS: The number of DDDs prescribed according to the GIP pharmacy records differed by only 8% from the number of DDDs calculated on the basis of notification to the NTR; 6889 patients should have been registered instead of 6349. CONCLUSION: The close correlation between the use of pyrazinamide as measured by the GIP and NTR provides strong evidence that in the Netherlands tuberculosis is reported in conformity with the guidelines for notifiable diseases. The method was simple to apply and may deserve follow-up in other countries.

Adolescent↗

PubMedDate not supplied

Effect of peritoneal dialysis on plasma and peritoneal fluid concentrations of isoniazid, pyrazinamide, and rifampin.

OBJECTIVE: This study was performed to elucidate the pharmacokinetic profiles of antimycobacterial regimens for peritoneal dialysis patients. PATIENTS: Nine patients on maintenance continuous ambulatory peritoneal dialysis (CAPD) were included in this study. METHODS: After administering a conventional oral dose of antituberculosis medications, we measured plasma and peritoneal fluid concentrations of isoniazid by fluorometry, and rifampin and pyrazinamide by high performance liquid chromatography. The assay data were subjected to pharmacokinetic analysis. RESULTS: Average peak plasma concentrations of isoniazid, rifampin, and pyrazinamide were 3.3 mg/L, 6.5 mg/L, and 30.9 mg/L, respectively, all of which much exceed the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis. Peritoneal fluid concentrations of isoniazid and pyrazinamide were maintained well above the MICs for M. tuberculosis; however, peritoneal fluid concentration of rifampin was below the therapeutic range most of the time. CONCLUSION: For the treatment of systemic or pulmonary tuberculosis in CAPD patients, no dose adjustments are required for isoniazid, rifampin, or pyrazinamide. On the contrary, for the treatment of tuberculous peritonitis, oral rifampin therapy is not expected to be effective because of its low peritoneal fluid concentration.

Adult↗

PubMed1989

Tubulointerstitial nephritis associated with pyrazinamide.

Modern antituberculous therapy consists of a combination of several drugs, some of which (e.g. rifampicin and streptomycin) may cause impairment of renal function. Pyrazinamide therapy has been associated with dose-dependent hepatotoxicity, hyperuricaemia, arthralgia and arthritis. The patient described in this report developed renal failure, fever, arthritis and arthralgia during administration of isoniazid, rifampicin, streptomycin and pyrazinamide. The renal biopsy showed tubulo-interstitial nephritis. After withdrawal of pyrazinamide, while continuing all other drugs, both renal function and histological findings improved which points to an association of renal failure with pyrazinamide.

Acute Kidney Injury↗

PubMed1988

Pyrazinamide and pyrazinoic acid pharmacokinetics in patients with chronic renal failure.

Pharmacokinetics of pyrazinamide and its major metabolite, pyrazinoic acid, were assessed in 10 chronic uremic patients treated by maintenance hemodialysis in comparison with 10 normal subjects. All subjects ingested a single dose of 1 g of pyrazinamide, the patients receiving the drug immediately after the end of a dialysis session. Bioavailability of pyrazinamide was only slightly increased in patients, its dialysis extraction coefficient being 55.3%. In contrast, pyrazinoic acid has an elimination rate-dependent metabolism with a bioavailability markedly increased in patients and a dialysis extraction coefficient of 59.8%. These data may lead to recommendations of a reduction in the dosage of pyrazinamide in dialysis patients. However, administering the usual dosage of the drug at the end of each dialysis session seems preferable to the daily administration of a reduced dosage.

Adult↗

PubMedDate not supplied

Determination of pyrazinamide in human by high performance liquid chromatography.

A facile and sensitive high performance liquid chromatographic (HPLC) technique has been developed for the determination pyrazinamide (PZA) in human plasma. Nicotinamide(NIA) is used as internal standard(IS). Plasma is deproteinized with 0.7 M perchloric acid; clear supernatant is neutralized with 1M NaOH and injected onto HPLC. The separation of pyrazinamide and the internal standard is carried out on a Supelco LC-18 (DB) column with a basic mobile phase. Pyrazinoic acid, the major metabolite, other anti-tuberculous drugs and endogenous components do not interfere with measurement of pyrazinamide. The limit of detection of pyrazinamide with this method is 0.2 mg/0.2 ml plasma (CV 8.2%).

Adult↗

PubMed2006

Variability in the population pharmacokinetics of pyrazinamide in South African tuberculosis patients.

OBJECTIVE: This study was designed to characterize the population pharmacokinetics of pyrazinamide in South African pulmonary tuberculosis patients, with special reference to interindividual and interoccasional variability (IIV and IOV, respectively). METHODS: Concentration-time measurements obtained from 227 patients receiving oral doses of pyrazinamide were pooled to create a dataset containing 3,092 data points spanning multiple dosing occasions. The software program NONMEM was used to analyze the data. RESULTS: A one-compartment model with first-order absorption, including a zero-order component describing release from formulation, and first-order elimination best described the data. The absorption rate constant was estimated to be bimodally distributed between two distinct subgroups, fast and slow, in approximately even proportion. Absorption rate was threefold greater in fast absorbers (3.56 h(-1)) in comparison to slow absorbers (1.25 h(-1)). Typical values of oral clearance and apparent volume of distribution were estimated as 3.42 L h(-1) and 29.2 l, respectively. IOV was supported in oral clearance (0.0238, variance) and absorption rate (0.623, variance). The duration of zero-order absorption was estimated as 0.290 h, and was quite variable between patients (0.957, variance). CONCLUSION: The absorption of pyrazinamide in the studied population was highly variable and two separate subpopulations were identified. IOV accounted for a proportion of the variability in clearance and the absorption rate constant.

Absorption↗

PubMed1987

Study of the metabolism of pyrazinamide using a high-performance liquid chromatographic analysis of urine samples.

A reversed-phase high-performance liquid chromatographic method was developed for the simultaneous determination of pyrazinamide and its metabolites in urine. Study of the metabolism of pyrazinamide by this method demonstrated that 5-hydroxypyrazinamide excretion was compatible with pyrazinoic acid excretion and allopurinol decreased in vivo conversion of pyrazinamide to 5-hydroxypyrazinamide and blocked that of pyrazinoic acid to 5-hydroxypyrazinoic acid.

Allopurinol↗

PubMed1989

Metabolism of pyrazinamide and allopurinol in hereditary xanthine oxidase deficiency.

The metabolism of pyrazinamide and allopurinol was studied in three xanthinuric patients from two families with hereditary xanthinuria to determine whether both substrates were oxidized only by xanthine oxidase or by other oxidases as well. One xanthinuric patient could neither metabolize pyrazinamide into 5-hydroxypyrazinamide nor allopurinol into oxypurinol. Two xanthinuric patients could metabolize both pyrazinamide into 5-hydroxypyrazinamide and allopurinol into oxypurinol but could not oxidize pyrazinoic acid to 5-hydroxypyrazinoic acid. These findings suggest that xanthinuria comprises at least two subgroups.

Adult↗

PubMed1978

The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide.

This paper reviews hepatic toxicity during chemoprophylactic treatment with isoniazid alone, and during the treatment or retreatment of active pulmonary tuberculosis with regimens containing one or more of the drugs isoniazid, rifampicin and pyrazinamide. Chemoprophylaxis with isoniazid carries a risk of drug-induced hepatitis, and this risk needs to be weighed against the advantages of preventing tuberculosis morbidity. The risks of hepatitis during standard treatment based on isoniazid are very small, and most patients who develop hepatitis recover. Moreover, it is often doubtful whether hepatitis is in fact drug-induced, and a proportion of patients who develop it already have liver disease at the time treatment is started. The risks are acceptable in the treatment of bacteriologically active disease. There is no consistent evidence that giving rifampicin with isoniazid in the initial treatment of tuberculosis increases the risk of hepatitis; in particular, transient abnormalities in the results of tests of liver function during the early weeks of treatment do not imply serious toxicity; patients who are rapid acetylators of isoniazid are not, as has been suggested, exposed to any special risk, and patients with known liver disease can also be treated without undue risk. Retreatment regimens based on rifampicin plus ethambutol carry a low risk of hepatitis, even though patients who need retreating have often experience toxicity during their initial treatment. Frist-line or second-line regimens containing pyrazinamide in currently accepted dosages, given daily or intermittently, carry a low and acceptable risk of hepatic toxicity. Finally, current studies of daily and intermittent short-course regimens based on isoniazid, rifampicin and pyrazinamide will extend our knowledge of hepatic toxicity. Because such regimens involve small total quantitites of drugs given over short periods they are likely to give rise to less hepatic toxicity than regimens of standard duration.

Acetylation↗

PubMed1987

Pyrazinamidase activity of Mycobacterium tuberculosis--a test of sensitivity to pyrazinamide.

Pyrazinamidase activity has been found to correlate with pyrazinamide sensitivity in strains of Mycobacterium tuberculosis. In vitro sensitivity to pyrazinamide in acidified Löwenstein-Jensen medium, and pyrazinamidase activity by the Wayne method, were determined in 378 clinical isolates of M. tuberculosis. A close correlation was observed between the results of both tests. This method of detecting pyrazinamidase activity was found to be a rapid, simple and reliable substitute for pyrazinamide sensitivity testing, and it overcomes the difficulty of growing M. tuberculosis at pH 5.5, as required in the standard method.

Amidohydrolases↗

PubMed2003

Photodegradation pathways and the in vitro phototoxicity of pyrazinamide, a phototoxic antitubercular drug.

The phototoxic antitubercular drug pyrazinamide (1) is photolabile under irradiation with UV-A light as well as with a N2 laser (at 337 nm) in aerobic conditions. Irradiation in methanolic and in aqueous solutions of 1 produces four and three photoproducts, respectively. Their formation involves primary alpha-cleavage between the excited carbonyl of the amido group and the aromatic ring followed by hydrogen abstraction and dimerization. Pyrazinamide was able to cause photohemolysis in human erythrocytes and peroxidation of linoleic acid. Inhibition of both processes on addition of reduced glutathione (GSH) or ascorbic acid suggests the involvement of radicals. The absence of inhibition of the photohemolysis and lipid peroxidation processes in the presence of sodium azide (NaN3), or irradiation under argon, and the absence of singlet oxygen during the photolysis confirmed with 2,5-dimethylfuran rules out the possibility of participation of 1O2 in this process. Glutathione depletion was also observed. A radical intermediate was evidenced by thiobarbituric acid that was used as a radical probe, as well as by the dimerization of cysteine. No photohemolysis was detected in presence of the isolated photoproduct. We have also determined the relative efficiencies for the formation of single strand breaks after the irradiation of pBR322 DNA and pyrazinamide, which was also reduced in the presence of GSH.

Antitubercular Agents↗

PubMed1998

-Skin eruption after the first dose of antitubercular quadri-therapy: consideration of pyrazinamide-.

UNLABELLED: We report a rash after the first dose of antituberculosis polytherapy which raises questions concerning procedures to be followed. CASE REPORT: An 8-year-old child presented with a pruritic rash 1.5 hours after the first dose of isoniazide, rifampicine, pyrazinamide and ethambutol was simultaneously administered, which did not recur after successive re-administration of isoniazide and rifampicine. Pyrazinamide, which was re-administered last, induced a recurrence. Slower pyrazinamide re-administration allowed continuation of treatment. CONCLUSION: A protocol for re-administration of the four drugs is suggested.

Antibiotics, Antitubercular↗

PubMed1998

Stability of bethanechol chloride, pyrazinamide, quinidine sulfate, rifampin, and tetracycline hydrochloride in extemporaneously compounded oral liquids.

The stability of five drugs commonly prescribed for use in oral liquids but not commercially available as such was studied. Bethanechol chloride 5 mg/mL, pyrazinamide 10 mg/mL, quinidine sulfate 10 mg/mL, rifampin 25 mg/mL, and tetracycline hydrochloride 25 mg/mL were each prepared in a 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus, and cherry syrup and placed in 120-mL amber clear polyethylene terephthalate bottles. Three bottles of each liquid were stored at 5 degrees C and three at 25 degrees C, all in the dark. Samples were taken initially and at various times up to 60 days for analysis by high-performance liquid chromatography and assessment of appearance and odor; pH was measured. A mean of at least 90% of the initial drug concentration was retained for 60 days in the liquids containing bethanechol chloride, pyrazinamide, or quinidine sulfate and for 28 days in the rifampin-containing liquids and the mixture of tetracycline hydrochloride and Ora-Sweet-Ora-Plus at both 5 and 25 degrees C. Tetracycline hydrochloride concentrations of 90% or more of the initial concentration were retained in the liquids prepared with Ora-Sweet SF-Ora-Plus for 10 days at 5 degrees C and 7 days at 25 degrees C and in those prepared with cherry syrup for 7 days at 5 degrees C and 2 days at 25 degrees C. No substantial changes in the appearance, odor, or pH of any liquid were observed. At 5 and 25 degrees C, bethanechol chloride 5 mg/mL, pyrazinamide 10 mg/mL, and quinidine sulfate 10 mg/mL were stable in three extemporaneously compounded oral liquids for 60 days and rifampin 25 mg/mL was stable for 28 days. The stability of tetracycline hydrochloride 25 mg/mL varied with the vehicle.

Administration, Oral↗

PubMed2000

High-performance liquid chromatographic determination of pyrazinamide in human plasma, bronchoalveolar lavage fluid, and alveolar cells.

A technique is presented for the measurement of pyrazinamide in human plasma, bronchoalveolar lavage, and alveolar cells by reversed-phase column chromatography. The assay utilizes acetazolamide as an internal standard, ultraviolet detection at 268 nm, and an acetonitrile-based mobile phase. Preparation of plasma samples requires a simple deproteinization step, resulting in the development of sharp peaks with retention times of 8.4 and 17 minutes for pyrazinamide and acetazolamide, respectively. Bronchoalveolar lavage and alveolar cell suspensions require an acid extraction with ethyl acetate, evaporation to dryness, and reconstitution. This method provides specific, rapid, and reliable determinations of drug concentrations and therefore is suitable for pharmacological studies, particularly those that are designed to quantitate the intrapulmonary concentrations of pyrazinamide.

Antitubercular Agents↗

PubMed1988

Cerebrospinal fluid pyrazinamide concentrations in children with tuberculous meningitis.

Cerebrospinal fluid pyrazinamide concentrations were determined by high pressure liquid chromatography in 53 samples from 13 children who had tuberculous meningitis complicated by increased intracranial pressure. Peak concentrations of up to 50 micrograms/ml were achieved between 1 1/2 and 2 1/2 hours after pyrazinamide administration and in most cases a concentration of 20 micrograms/ml or more was achieved. We conclude that pyrazinamide easily gains entry into the cerebrospinal fluid of children with tuberculous meningitis and should be included in treatment regimens for that disease.

Child, Preschool↗

PubMed2026

The effect of metformin on the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide in adults with tuberculosis.

Metformin is under investigation as adjunctive host-directed therapy for tuberculosis (TB), which might interact with first-line TB treatment. We used population pharmacokinetic modeling to assess whether metformin alters first-line TB-drug pharmacokinetics in HIV/TB-coinfected adults without diabetes. Rifampicin, isoniazid, and pyrazinamide pharmacokinetics were investigated in participants from a randomized clinical trial of adjunctive metformin (500 mg twice daily to week 12) in adults starting HIV-associated TB treatment. Antiretroviral therapy (ART)-naïve participants initiated dolutegravir-based ART within 8 weeks. Intensive and semi-intensive sampling was conducted at week 5; concentration-time data were analyzed using non-linear mixed-effects modeling. Data from 78 individuals (43 receiving metformin, median weight 60.8 kg, 62.8% male, 79.5% on ART) were analyzed. Rifampicin and pyrazinamide were described by one-compartment models with linear elimination; typical clearances were 15.8 L/h (95% CI: 13.5-18.7) and 3.88 L/h (95% CI: 3.54-4.08), respectively. Isoniazid followed a two-compartment model with a mixture model for acetylator status; clearance was 10.5 L/h (95% CI: 9.44-11.9) in slow acetylators and 28.8 L/h (95% CI: 25.6-31.0) in fast/intermediate acetylators. Metformin reduced isoniazid bioavailability by 15.6% (95% CI: 4.45-26.4%, P < 0.009) and rifampicin bioavailability by 24.0% (95% CI: 7.83-36.3%, P < 0.007), decreasing the area under the curve from 0 to 24 h from 18.2 to 15.6 mg·h/L and from 35.9 to 27.1 mg·h/L, respectively. No significant effect on pyrazinamide was detected. We found that non-diabetic patients on metformin had lower isoniazid and rifampicin bioavailability. Lowered rifampicin exposure might be clinically relevant; simulations suggest that this could be offset by a single 150 mg rifampicin dose.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04930744.

Humans↗

PubMed1986

Evaluation of a radiometric method for pyrazinamide susceptibility testing of Mycobacterium tuberculosis.

Pyrazinamide susceptibility testing of Mycobacterium tuberculosis requires an acid environment. By controlling the method of acidification and the quality and quantity of the inoculum, the test can be performed with the BACTEC radiometric system (Johnston Laboratories, Towson, Md.). We acidified BACTEC 7H12 medium with buffered phosphoric acid and adjusted the test inoculum to 1/10 of that usually employed in BACTEC protocols; after 5 days of growth we correctly identified 36 of 36 strains susceptible to 50 micrograms of pyrazinamide per ml. All 18 resistant strains were classified as pyrazinamide resistant. (Susceptibility or resistance had been determined by standard plate assays.) The test was able to detect small resistant populations in artificial mixtures of 1 or 2% resistant bacteria with a susceptible strain (10 mixtures each). We tested 70 M. tuberculosis strains in acidified BACTEC 7H12 medium and by the plate dilution test at pH 5.5. All strains grew in the BACTEC medium, but three strains failed to grow on plates and were not tested further; the results of both methods agreed for the remaining strains.

Culture Media↗

PubMed1995

In vitro antimycobacterial activities of pyrazinamide analogs.

We synthesized various pyrazine derivatives and pyrazinamide analogs and assayed their antimycobacterial activities in vitro in order to find new drugs which are more active against Mycobacterium tuberculosis than pyrazinamide and also active against Mycobacterium avium and Mycobacterium intracellulare. Of the drugs synthesized, four drugs, namely, pyrazine thiocarboxamide, N-hydroxymethyl pyrazine thiocarboxamide, pyrazinoic acid n-octyl ester, and pyrazinoic acid pivaloyloxymethyl ester, were not only bacteriostatic but also bacteriocidal against these three species of mycobacteria in vitro under conditions in which pyrazinamide showed no or little activity. In conclusion, these four drugs are possible candidates for new antimycobacterial agents, and animal experiments are now under way.

Antitubercular Agents↗