Isoniazid Levels Research Articles

Modulation of CYP2E1 activity by isoniazid in rapid and slow N-acetylators.

An investigation was undertaken to compare the effects of isoniazid pretreatment on the CYP2E1-mediated 6-hydroxylation of chlorzoxazone in healthy subjects of known N-acetylator phenotype. CYP2E1 activity was estimated based on the 6-hydroxylation of chlorzoxazone following single dose (250 mg) oral administration to seven slow and eight rapid N-acetylators who were in good health. Separate studies were performed prior to and 14 days after the subjects received 300 mg isoniazid daily. Additional investigations were undertaken 2 and 16 days after discontinuing treatment with the antitubercular agent. Concomitant administration of chlorzoxazone with the final dose of isoniazid resulted in reduced metabolism in both phenotypes; however, the extent of inhibition of 6-hydroxylation was greater in the slow N-acetylators-about 80% vs 60%. Two days after stopping isoniazid administration, chlorzoxazone's pharmacokinetic parameters had returned to their baseline values and remained constant for a further 14 days in the rapid acetylators. In contrast, chlorzoxazone's 6-hydroxylation in slow acetylators was increased by about 60% compared with baseline at 2 days after discontinuing isoniazid but had returned to its initial value 14 days later. The interphenotypic difference in the time-dependent interactions of isoniazid with CYP2E1 probably reflect a higher drug exposure in slow acetylators. Inhibition of CYP2E1 activity occurs in both N-acetylator phenotypes but is less extensive in fast acetylators, during the time that effective levels of isoniazid are present in the body. Increased CYP2E1 activity reflective of enzyme induction, on the other hand, is only observable following isoniazid's elimination and is more extensive in slow than rapid acetylators. Even then, however, such induction is relatively modest and of short duration.

Maintenance of therapeutically active levels of isoniazid for prolonged periods in rabbits after a single implant of biodegradable polymer

Setting: Poor patient compliance is the serious limiting factor in the chemotherapy of tuberculosis. Objective: To solve this problem we have been developing depot-drug delivery of antimycobacterial drugs. Earlier studies with mice using isoniazid in polylactic-co-glycolic acid (PLGA) co-polymer have shown that a single implant of the polymer could ensure sustained levels of free isoniazid for up to 8 weeks. Similar studies were now undertaken in rabbits. Design: The biodegradable PLGA polymer rods containing isoniazid were implanted on the back of the rabbits under anaesthesia in an isoniazid dose of 90 mg/kg. Concentrations of isoniazid and acetylisoniazid in serum and urine were determined by the high-performance liquid chromatography (HPLC) method at close intervals up to 96 h to study the burst-size, and later at weekly intervals up to 9 weeks to study the sustained levels. Results and conclusions: There was no abnormal release of isoniazid in the earlier periods. Concentrations of isoniazid ≥ 0.2 μg/ml were found both in serum and urine up to 63 days after implant. Urine specimen obtained at 6 weeks after giving the implant inhibited the growth of Mycobacterium tuberculosis in vitro as measured by the radiometric (Bactec) method. These findings in non-rodent animal species confirm the usefulness of the depot-drug delivery method of drug administration and warrant hopes for the successful treatment of tuberculosis avoiding the problem of non-compliance.

Experimental chemotherapy of tuberculosis using single dose treatment with isoniazid in biodegradable polymers.

In previous studies we showed that a single implant of polylactic-co-glycolic acid (PLGA) polymer as a film containing isoniazid ensured sustained release of the drug for up to 4 weeks. These studies have been extended to PLGA polymer as a rod which is retrievable. Both types of implant gave therapeutically active levels of free isoniazid in liver and urine for prolonged periods. We assessed the in vivo chemotherapeutic efficacy of the rod implant against heavy infections of virulent Mycobacterium tuberculosis in C57Bl/6 mice. The chemotherapeutic data essentially confirmed the bioavailability data. In one chemotherapeutic study, one (7%) out of 15 mice which received the isoniazid polymer implant died within 30 days of bacterial challenge, while none of those receiving daily oral treatment died. In contrast, 14 (93%) of the 15 control mice died during the same period. In a second study similar results were obtained.

The Paradoxical Anticonvulsive and Awakening Effect of High-Dose Pyridoxine Treatment for Isoniazid Intoxication-Reply

In Reply.— De' Clari raises some interesting points regarding the potential awakening effect of pyridoxine and makes an argument for pyridoxine infusions in comatose isoniazid-poisoned patients. There are two likely mechanisms by which pyridoxine may reverse isoniazid-induced coma. First, pyridoxine is a cofactor in the transamination reaction between γ-aminobutyric (GABA) and a-ketoglutaric acid—a reaction responsible for GABA degradation. 1 The second mechanism is based on de' Clari's observation of a rapid efflux of isoniazid from the peripheral to the vascular compartment. This efflux would provide a mechanism for a reduction of central nervous system isoniazid levels. By binding to isoniazid (as pyridoxine is known to do), 2 the levels of active circulating isoniazid may be reduced. It is unknown to what degree these two mechanisms are operative in reducing the depth and duration of isoniazid-induced coma. We have some concerns regarding a continuous infusion of pyridoxine for comatose patients. One

Seruim rifampin and isoniazid levels in children with tubercular infections

Seruim rifampin and isoniazid levels in children with tubercular infections

Salivary levels of isoniazid and rifampicin in tuberculous patients

Concentrations of isoniazid and rifampicin were determined in time-matched samples of saliva and serum from 30 tuberculous patients (18 with pulmonary tuberculosis and 12 with intestinal tuberculosis), comprising 18 slow and 12 rapid acetylators of isoniazid, following administration of isoniazid 300 mg and rifampicin 12 mg/kg. The diffusion of isoniazid into saliva was quite rapid and the salivary concentrations were similar to those in serum, suggesting that saliva could be used in place of serum for all pharmacokinetic studies with isoniazid. The salivary concentrations of rifampicin were much lower than those in serum, the mean peak concentrations being 0.9 and 8.5 μg/ml, respectively. Further, there was evidence of a significant delay in the diffusion of rifampicin from serum to saliva.

Emergency department management of children with acute isoniazid poisoning

We suggest that the following therapeutic regimen be followed in cases of isoniazid poisoning in children. In cases of intractable seizure activity in a child which remains unexplained, consider isoniazid poisoning. Give pyridoxine as an intravenous bolus to all children in whom isoniazid toxicity is suspected, who exhibit seizure activity and are known to have been exposed to isoniazid, or who have a history of ingesting one gram or more of isoniazid. It should be given on a gram-for-gram basis, and the clinician need not await serum isoniazid levels before administering pyridoxine. It can be safely given at a rate of five grams per three minutes in a 50 ml volume. In fact, serum isoniazid determinations are not available in many emergency departments and have not been shown to correlate closely with symptomatology. When available, serum isoniazid levels at best are subject to variability owing to sampling procedures (serum protein must be removed within two hours of sampling). The result is that serum isoniazid levels play only a minor role in the emergency department management of isoniazid poisoning. To potentiate the antidotal effects of pyridoxine, diazepam (0.1 mg/kg) may be given intravenously, preferably at a second intravenous site. Because the lactic acidosis seen after seizures resolves spontaneously, and because metabolic alkalosis may result following excess lactate loading, administration of bicarbonate is usually not necessary, and may be harmful in some cases. After pyridoxine treatment, syrup of ipecac may be given to empty the stomach.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibiotic uptake by alveolar macrophages of smokers.

Cigarette smoking, particularly when associated with chronic pulmonary disease, increases the risk of respiratory tract infection. Thus, we elevated the uptake of antibiotics by alveolar macrophages (AM) obtained by bronchoalveolar lavage from persons who smoke and have associated pulmonary abnormalities, circumstances which adversely affect certain macrophage functions. The entry of radiolabeled drugs into AM was determined by a velocity-gradient centrifugation technique, and uptake was expressed as the ratio of cellular to extracellular antibiotic concentration (C/E). Cefamandole and penicillin G were taken up poorly by the AM obtained from smokers (C/E less than or equal to 1). Cellular levels of isoniazid, gentamicin, and tetracycline were similar to their extracellular concentrations. The lipid-soluble drugs lincomycin, chloramphenicol, and rifampin were concentrated severalfold by the AM from smokers (C/E = 3 to 11). Ethambutol also entered macrophages readily (C/E = 11). Erythromycin and clindamycin were massively concentrated by the AM from smokers (C/E = 23 to 56). The AM of smokers accumulated a lipid-soluble antibiotic (rifampin) and actively transported agents (erythromycin propionate, clindamycin) more avidly than did the AM of nonsmokers. Augmented uptake of these antibiotics by the AM of smokers may be related to structural and functional alterations induced by smoking.

Metal binding by pharmaceuticals. Part 3. Copper (II) and zinc (II) interactions with isoniazid.

Formation constants for copper(II) and zinc(II) complexes of isonicotinoylhydrazine (isoniazid) and guanosine-5'-monophosphate have been measured potentiometrically at 37 degrees C, I = 150 mmol dm-3 [NaCl]. These constants have been used in computer models to assess the extent of complex formation by the drug in vivo. The simulations indicate that the predominant complexes existing in blood plasma are ternary species formed with histidinate. However, at clinical levels of isoniazid, it seems unlikely that these complexes are physiologically significant. On the other hand, ternary complex formation with nucleosides may be involved in the binding of isoniazid to viral RNA.

Isoniazid disposition, comparison of isoniazid phenotyping methods in and acetylator distribution of Japanese patients with idiopathic systemic lupus erythematosus and control subjects.

1 Plasma levels of isoniazid (INH) and acetyl INH in plasma were measured with a spectrofluorometric method, and INH and its metabolites (acetyl INH, mono-acetylhydrazine, diacetylhydrazine and free hydrazine) excreted in urine were measured with a gas chromatography-mass spectrometry, respectively, after an oral dose of INH 10 mg/kg in 19 Japanese patients with idiopathic systemic lupus erythematosus (SLE) and in the same number of healthy controls. 2 When phenotyped according to various methods previously reported, 16 to 18 of the SLE and 17 to 19 of the control group were rapid acetylators. Regardless of the phenotyping methods applied, the distribution of acetylator phenotype of SLE patients was not significantly different from the control group or from the data previously reported among normal Japanese population. 3 By phenotyping our subjects with an INH T 1/2 of 110 min or less as rapid acetylators, and more slow acetylators, 3 of SLE patients and 2 of the controls were slow, while the remainder were all rapid. When this antimode was used, the mean apparent kinetic variables of INH and acetyl INH estimated from the plasma concentration-time data and the mean values for the 24-h urinary amount of INH and its metabolites, except for monoacetylhydrazine (P less than 0.05), did not significantly differ between the rapid acetylators of SLE and control groups. 4 The distribution of INH T 1/2, acetyl INH to INH ratios in plasma and urine, values in urine for log10 (diacetylhydrazine to monoacetylhydrazine) and for diacetylhydrazine to INH or acetyl INH was similar between the two groups except for one patient who was definitely classified as a slow acetylator regardless of whichever phenotyping methods were used. The excretory patterns of hydrazine compounds reflect, in general, the inactivating ability of INH in each individual. 5 The data suggest that phenotyping by using plasma samples is, in general, better than by using urine samples. The plasma T 1/2 alone is the most satisfactory criterion. 6 We conclude that neither INH disposition nor phenotype distribution assessed by the reported methods using INH as the test compound are altered in idiopathic SLE, and that a search for racial and/or geographical factor(s) likely to result in autoimmune disease may give a clue to the pathogenesis in addition to further exploration for the possible interrelation between idiopathic SLE and genetic slow acetylation.

Tissue distribution of isoniazid and its metabolites in rats.

Distribution of isoniazid and its metabolites was observed in the liver, kidney, lung and plasma after the subcutaneous administration of isoniazid to rats. The tissue levels of isoniazid, acetylisoniazid, acetylhydrazine, 1,2-diacetylhydrazine and hydrazine were determined by mass fragmentography using a gas chromatograph-mass spectrometer equipped with a multiple ion detector-peak matcher. Using the compounds labeled with a stable isotope as an internal standard, namely the isotope dilution method, made it possible to estimate trace amounts of these metabolites in the tissues. The amount of hydrazine was much less than the other hydrazines, but the metabolite which is well known as a mutagen, could be successfully detected in the tissues and plasma. The greater part of free hydrazine is formed through a direct hydrolysis of isoniazid. The isoniazid-hydrolyzing activity was found to be significantly higher in the liver homogenate. This suggested that hydrazine formation is mainly caused by hepatic hydrolysis.

High-Performance Liquid Chromatographic Determination of Isoniazid and 1 -Isonicotinyl-2-lactosylhydrazine in Isoniazid Tablet Formulations

A high-performance liquid chromatographic procedure is presented for the simultaneous determination of isoniazid and 1-isonicotinyl-2-lactosylhydrazine (I) in isoniazid tablet formulations. An aliquot of a diluted aqueous tablet extract is introduced onto a microparticulate cyanopropyl bonded-phase column using a valve-loop injector and chromatographed using a mobile phase of acetonitrile-0.01 M, pH 3.5 aqueous acetate buffer (5:95). Compound I can be determined at levels as low as 0.5% of the isoniazid label claim. The relative standard deviations are 0.4 and 0.7% for the simultaneous determination of isoniazid and I, respectively. Seven commercial tablet formulations contained 93.8-97.0% of the labeled isoniazid amounts and 0.3-5.8% of I, expressed as equivalent isoniazid relative to the labeled isoniazid level.

Effect of ethanol on levels of isoniazid, sulfanilamide and sulfapyridin in mouse blood

The effect of ethanol of blood levels of free and conjugated sulfonamides (sulfanilamide and sulfapyridin) and isoniazid was investigated in mice. Ethanol (1.5 and 4 mg/g i.v.) enhanced the amount of conjugated isoniazid without affecting the total amount of isoniazid in blood, and tended to raise the total amount of the sulfonamides.

Blood levels of rifampicin, desacetylrifampicin and isoniazid during combined therapy.

Blood levels of rifampicin, desacetylrifampicin and isoniazid during combined therapy.

Granulomatous hepatitis and pleuritis after ileal bypass for obesity

A patient is presented who developed a granulomatous hepatitis and pleuritis approximately 7 months after an ileal bypass procedure for morbid obesity. Although the etiological agent was presumed to be Mycobacterium tuberculosis no pathogenic organism was grown from the liver, pleura, bone marrow, sputum, or gastric aspirate. The possibly increased susceptibility of these patients to mycobacterial infections is discussed. The value of obtaining serum levels of ethambutol, isoniazid, and rifampin, in patients with malabsorption is stressed. Although this patient seemed to respond to antituberculous therapy, other possible causes for the granulomatous process are explored.

CONTROL OF STREPTOMYCIN AND ISONIAZID IN MALNOURISHED CHILDREN TREATED FOR TUBERCULOSIS

In 12 malnourished children, who were treated for tuberculosis, plasma levels of streptomycin and isoniazid were followed. Streptomycin was administered i.m. in a dose of 25-50 mg/kg/24 hours. High initial plasma levels were reached (mean: 44.3 mug/ml at 30 min). Streptomycin levels were followed for 5 hours and the mean plasma level at that time was 17.0 mug/ml. From the present data a plasma half life of streptomycin of 3.5 hours has been estimated. It is advised that streptomycin should not be given in doses above 25 mg/kg/24 hours to avoid potential toxic plasma levels especially if plasma levels cannot be measured. It is also concluded from our study that renal function is not affected in malnourished children to an extent where streptomycin clearance is greatly affected. Isoniazid was given orally, 10 mg/kg/24 hours. From 30 min to 6 hours after administration, mean plasma levels of isoniazid above 0.5 mug/ml were observed. In all children measurable plasma levels were obtained. It is concluded that also children with malnutrition can absorb isoniazid after oral administration. From our data it is suggested that the majority of the children in our study were rapid inactivators of isoniazid.

Studies of serial plasma isoniazid concentrations with different doses of a slow-release preparation of isoniazid

The suitability of a slow-release matrix preparation of isoniazid for use in once-weekly chemotherapy has been investigated in South Indian patients. Serial plasma isoniazid concentrations were determined up to 6 hours following doses of 15, 30, 45 and 60 mg/kg body-weight in rapid inactivators and up to 10 hours following doses of 15, 30 and 45 mg/kg in slow inactivators. The isoniazid levels were sustained, and the peak concentrations (per unit dose) were considerably lower than with ordinary isoniazid. It was estimated that a matrix isoniazid dose of 35 mg/kg in slow inactivators and 50 mg/kg in rapid inactivators would produce a peak similar to that attained with a non-toxic dose of ordinary isoniazid 15 mg/kg in slow inactivators.A second investigation showed that matrix isoniazid 40 mg/kg in rapid inactivators produced a coverage (with 0–2 Ntg/ml) and exposure similar to those attained in slow inactivators with a highly effective dose of ordinary isoniazid 15 mg/kg, while 30 mg/kg gave substantially lower values. In both investigations, disproportionately large increases in plasma isoniazid concentrations were observed in rapid inactivators with an increase in the matrix isoniazid dose. In slow inactivators, both doses of matrix isoniazid, 30 and 40 mg/gk, resulted in coverage and exposure that were substantially higher than those obtained with ordinary isoniazid 15 mg/kg.

An improved micro spectrofluorometric assay for determining isoniazid in serum

A highly sensitive micro modification of a fluorometric procedure for measuring isoniazid levels in serum is described. This modification permits the use of as little as 25 μl of serum and simplifies the measurement of isoniazid in infants, primates, and small laboratory animals.

Isoniazid-Induced Acne and Pellagra

Seven patients with acneiform eruptions associated with isoniazid therapy, one of whom also had pellagra, were studied to determine whether they were slow or fast inactivators of isoniazid. Five patients, from 32 to 48 years of age, who had extensive eruptions were slow inactivators, as determined by the serum level of isoniazid six hours after administration and by serum half-life determination. Two patients, who were under 30 years of age and who had preexisting acne vulgaris and mild flares, were slow inactivators by serum half-life determination and were fast inactivators by six hour serum level determinations. Although not conclusive, the data are consistent with the hypothesis that slow inactivation of isoniazid is a significant determinant in those patients whose eruptions conform to the criteria discussed.

Blood levels of isoniazid and of its methan sulphonate derivative in rapid and slow inactivators after oral administration

Blood levels after oral administration of isoniazid and its metharesulphonate derivative (methaniazid) were compared in a group of 20 subjects consisting of 10 ‘rapid’ and 10 ‘slow’ inactivators. The two drugs were administered orally at the dose of 5 mg/kg., calculated as isoniazid: blood samples were withdrawn after three, six and nine hours and assayed with the vertical diffusion method using Mycobacterium tuberculosis H37Rv as test organism. Statistical analysis of the data showed that in rapid inactivators the blood levels reached after administration of methaniazid were significantly higher than those obtained with isoniazid (P<0.001). In slow inactivators the difference of the blood levels obtained with the two drugs did not reach a significant level (0.10>P>0.05). Sur un groupe de 20 individus, dont 10 inactivateurs ‘rapides’ et 10 ‘lents’, on a recherché les avantages de l'administration ‘per os’ du derivé methanesulfoné de l'isoniazide par rapport à l'isoniazide. Les deux produits ont été administrés à la posologie de 5 mg/kg d'isoniazide et les taux sanguins de produit actif ont été comparé 3. 6 et 9 heures après l'administration. L'analyse statistique des résultats montre que chez les inactivateurs rapides les taux sanguins après administration de methaniazide sont significativement plus élevés que ceux obtenus aprés administration, d'isoniazide (P<0.001). Chez les inactivateurs lents par contre, la différence des taux sanguins des deux médicaments n'atteint pas le taux de signification (0.10>P>0.05). En un grupo de 20 individuos. 10 inactivadores rápidos y 10 inactivadores lentos, se compararon los niveles sanguineos alcanzados despues de administrar isoniazida, y su derivado methanesulfonato (methaniazida). Ambas drogas se administraron oralmente, a la dosis de 5 mg./kg. calculadas en isoniazida; se obtuvieron muestras de sangre a las tres, seis y nueve horas y se empleó el método de difusión vertical usando el Mycobacterium tuberculosis H37Rv como germen testigo. El análisis estadístico de los datos mostró que en los inactivadores rápidos el nivel sanguíneo alcanzado despues de administrar methaniazida era significativamente más elevado que cuando se daba isoniazida (P<0.001). En los inactivadores lentos la diferencia de los niveles sanguineos obtenida con las dos drogas no fué estadísticamente significativa (0.10.>P>0.05).