Bcg vaccine may not be effective during isoniazid therapy. Pdf isoniazid metabolism and hepatotoxicity researchgate. Isoniazid may increase the formation of the potentially nephrotoxic inorganic fluoride metabolite of enflurane when used concomitantly. Paracetamol, 500 mg, was given before isoniazid, on day 7 of isoniazid administration, and 2 days after the last dose of isoniazid. The mechanism is unknown but may involve a reactive metabolite of the drug.
Inh metabolism has been thought to be associated with inhinduced. Mar 22, 2021 isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels. Determination of clinical factors affecting isoniazid pharmacokinetics and metabolic pathways. Isoniazid pharmacokinetics in children treated for respiratory. Metabolism of isoflurane in patients receiving isoniazid. Pdf on jan 1, 2007, fazlul huq published metabolism of isoniazid a molecular modeling analysis find, read and cite all the research you need on researchgate. Thus, though inh, rifampicin and pyrazinamide each in. The risk or severity of serotonin syndrome can be increased when isoniazid is combined with methotrimeprazine. Itcan be prevented by administration of pyridoxine whenever isoniazid is given. These metabolites of inh increase the levels of intracellular reactive. No hepatotoxicity has been described for ethambutol or streptomycin. Isoniazid decreases the metabolism of carbamazepine, thus slowing down its clearance. With its virtual lack of toxicity in the recommended doses of 3 to 5 mg. Following mycobacterium tuberculosis infection, up to 50% of infants isoniazid and metabolites of isoniazid viz.
Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome p450 3a5 anesthesiology march 2005 new insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development part 2. An evaluation of the in vitro roles and mechanisms of. Isoniazid inh, isonicotinyl hydrazide, an antituberculous drug, also causes liver damage in some patients at therapeutic doses. Determination of clinical factors affecting isoniazid pharmacokinetics and metabolic pathways in hiv co. Isoniazid inhibits hepatic metabolism of carbamazepine and phenytoin, resulting in increased anticonvulsant concentrations and toxicity in some patients. Tuberculosis is the most common cause of death in hivinfected patients. Isoniazid therapy is often associated with minor, transient and asymptomatic elevations in serum aminotransferase levels but, more importantly, isoniazid is a well known cause of acute clinically apparent liver injury which can be severe and is sometimes fatal. Isoniazid was oxidized by activated leukocytes to isonicotinic acid. Patients on concomitant efavirenzbased antiretroviral therapy had 64% and 80% higher population. From 50% to 70% of a dose of isoniazid is excreted in the urine within 24 hours, mostly as metabolites.
This is the classic textbook pattern of distribution into fast and slow acetylators figure 5. Sep 01, 2016 isoniazid inh is highly effective for the management of tuberculosis. Adverse effects of antitubercular therapy are sometimes potentiated by multiple drug regimens. The major routes of metabolism for isoniazid are acetylation to give acetylisoniazid, followed by hydrolysis to yield isonicotinic acid. Previously we reported that, depending on the condition, inh inhibits or induces the toxic pathway of apap metabolism. Isoniazid is still, 60 years after its introduction, a main front line drug for treating tuberculosis. The metabolism of isoniazid can be decreased when combined with chlorzoxazone. Aminosalicylic acid on the metabolism of isoniazid by man. To define the pharmacokinetics of isoniazid inh in children with tuberculosis in relation to. Genetics of isoniazid metabolism in caucasian, negro, and. Isoniazid and iproniazid metabolic activation european.
Its metabolism has been the subject of important research, much of which has focused on the. Isoniazid diffuses throughout total body water, even the central nervous system. Isoniazid inh remains a mainstay for the treatment of tuberculosis. Based on these findings, we conclude that under induced conditions, cyp2e1 is a primary enzyme involved in liver, but not kidney, formation of 19hete. Due to its genetic polymorphism, patients can be classified as slow, fast or intermediate acetylators. The frequency of rapid and slow alleles in caucasian and negro populations was similar and differed from that of a japanese population. However, variability in isoniazid pharmacokinetics can result in hepatotoxicity or treatment failure. The plasma halflife of isoniazid in patients with normal renal and hepatic function ranges from 14 hours, depending on the rate of metabolism. Isoniazid tablets, usp rx only warning severe and sometimes fatal hepatitis associated with isoniazid therapy has been reported and may occur or may develop even after many months of treatment. Jul 17, 2015 detailed pharmacokinetic studies undertaken on a slow and a rapid acetylator of isoniazid enabled approximate firstorder rate constants to be calculated for the metabolic processes involved in the conversion of isoniazid to acetylisoniazid, isonicotinic acid, isonicotinylglycine, monoacetylhydrazine, and diacetylhydrazine, and their excretion in the urine. Alarge variation in the metabolism of isoniazid was. The effect of isoniazid given daily for 7 days on paracetamol acetaminophen kinetics and metabolism was studied in 10 healthy volunteers. Rifater rifampin, isoniazid and pyrazinamide tablets. However, inh also frequently results in liver toxicity and peripheral neuropathy 1, 2, and its metabolism and bioactivation are thought to be.
The isoniazid induced peripheral neuropathy occurring in adult tuberculous patients results from a deficiency of biologically active pyridoxine. Population pharmacokinetic analysis of isoniazid, acetylisoniazid. Pdf isoniazid inh is highly effective for the management of tuberculosis. Effect of prednisolone and rifampin isoniazid metabolism. The deficiency is caused by the combination of isoniazid and pyridoxine to form a hydrazone which is excreted in the urine.
Inh can generate toxic reactive metabolites, thus playing a major role in drug metabolism and the pathophysiology of druginduced liver injury aubert et al. Dosage of isoniazid and rifampicin poorly predicts drug. The cytochrome p450 cyp 2e1 isoenzyme appears to be a predominant enzyme responsible for human oxidative enflurane metabolism. The variations in rate of isoniazid inactivation and elimination in different rapid and slow acetylator phenotypes are primarily due to. Isoniazid is metabolised primarily by the enzyme nacetyltransferase2. We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. The role of metabolism in the hepatotoxicity of isoniazid and iproniazid.
Inh is mainly dependent on nat2 pharmacogenomics, nat2 polymorphisms alter the pk of the parent drug. The tuberculostatic agent isoniazid has been implicated in inducing various idiosyncratic reactions including druginduced lupus. The major pathway of isoniazid metabolism was acetylation. At therapeutic levels isoniazid is bactericidal against actively growing intracellular and extracellular mycobacterium tuberculosis organisms. Isoniazid injection fda prescribing information, side. Metabolic aspects and toxicological correlates bentham.
Pharmacokinetics of isoniazid metabolism in man springerlink. The potent antituberculous effects of this drug have quickly been applied in clinical practice. Genetic control of isoniazid metabolism in man the bmj. Isoniazid may decrease the excretion rate of choline c 11 which could result in a higher serum level. Decreases gastrointestinal absorption of isoniazid. A stronger inhibition of uptake resulted when labeled isoniazid and. Isoniazid hepatotoxicity journal of pharmacology and. This metabolism combined with isoniazid s early bactericidal activity that is restricted to the first 24daysof. These studies have shown that there is rapid and complete absorption ofthedrug,giving aninitial high bloodlevel. Isoniazid and pyrazinamide are potentially hepatotoxic drugs. Pronounced interindividual variation in circulating isoniazid concentration and clearance which occur after dosing with the drug are associated with hereditary differences in the acetylalor status. Isoniazid metabolism and hepatotoxicity sciencedirect. Nacetyltransferase nat enzyme in humans and its metabolism was important in establishing the early observations on pharmacogenetics since its. Slow acetylators are at a greater risk for drugrelated toxicities because of the drugs long t.
Isoniazid inh is the most widely recommended agent for preventing tb disease in children. When the bacterial strain becomes resistant to one. Whenthis falls the greaterpart ofthecompound appears in the urine within 24hours oforal administration elmendorf et al. Assuming that elimination of isoniazid follows firstorder kinetics, the rate constant for elimination of isoniazid andthe halflife ofisoniazid werecalculated onthebasis oftheconcentrations at2, 3, 6, and8hin slow inactivators, and at 2, 3, and 6 h only in rapid inactivators as someofthemhadindeterminate concentrations metabolism of isoniazid can be decreased when combined with methotrexate. To investigate the effect of watercress on the metabolism of chlorzoxazone, an in vivo probe for cyp2e1, the oral pharmacokinetics of chlorzoxazone was studied in 10 healthy volunteers before and after a single ingestion of a watercress homogenate 50 gm. Inhibition of the metabolism of paracetamol by isoniazid. Second, the included patients were not genotyped for drug metabolism enzyme or transporter polymorphisms. Concomitant use with isoniazid may reduce the metabolism of theophylline, thereby increasing its plasma levels. Uptake of the drug by cells in a sauton environment containing 0. A third chlorzoxazone pharmacokinetic study was performed after a 1. Common side effects include problems with vision, joint pain, nausea, headaches, and feeling. Inhibition of chlorzoxazone metabolism, a clinical probe for. Isoniazid solution isoniazid dose, indications, adverse. Isoniazid inh is an antituberculosis drug associated with idiosyncratic liver.
The major route of isoniazid metabolism is hepatic acetylation by nacetyl transferase which produces acetylisoniazid. Acetyisoniazid is further hydrolysed to isonicotinic acid and acetylhydrazine, both of which are excreted in the urine. The relationship between the hepatotoxicity and metabolism of isoniazid and its metabolites, acetylisoniazid and acetylhydra zine, has been investigated. Detailed pharmacokinetic studies undertaken on a slow and a rapid acetylator of isoniazid enabled approximate firstorder rate constants to be calculated for the metabolic processes involved in the conversion of isoniazid to acetylisoniazid, isonicotinic acid, isonicotinylglycine, monoacetylhydrazine, and diacetylhydrazine, and their excretion in the urine. The two medications are likely to be taken concurrently. Pdf population pharmacokinetic analysis of isoniazid. Various drugs have been used for the treatment of antitubercular treatment. Isoniazid toxicity is associated with a high mortality rate.
Inh and 10 mm pza by reducing oxidative damage to mitochondria. Further studies of the metabolism of isoniazid were carried out on another 17 slow and 11 rapid acetylators. Get a printable copy pdf file of the complete article 1. The effect of acetaminophen on isoniazid metabolism ubc. The potential for clinically important interactions exists because this drug is a potent inhibitor of drug metabolism. However, it can cause liver injury and even liver failure. Isoniazid is the most reliable and most commonly used medication for tuberculosis. Isoniazid decreased liver and kidney 20hete content to 34 10% and 15. Shayakhmetova new theories for isoniazid hepatotoxicity et al. Mechanism for the pyridoxal neutralization of isoniazid. Drug metabolism in the liver university of washington. Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. Studies on the metabolism of isoniazid ats journals. In patients who are genetically fast acetylators, isoniazid may not reach therapeutic levels and will have a short plasma t.
Isoniazid metabolism and hepatotoxicity pengcheng wang a, komal pradhan a, xiaobo zhong b, xiaochao ma a, n a center for pharmacogenetics, department of pharmaceutical sciences, school of. Among the metabolites of isoniazid, hydrazine plays the major role in hepatotoxicity and is known to cause irreversible hepatic cellular damage 8. Studies and case reports have shown that isoniazid inhibits the metabolism of several drugs. Dec 17, 2020 isoniazid is still widely used for the treatment of tuberculosis, but iproniazid is now rarely used as an antidepressant. Inh metabolism has been thought to be associated with inhinduced liver injury. The role of metabolism in the hepatotoxicity of isoniazid and. Isoniazid active learning template medication laura lopez. It is usually given in combination with other tuberculosis medications, such as isoniazid, rifampicin and pyrazinamide. Drug metabolism cytochrome p450 conjugation drug transporters liver metabolism phase i, ii, and iii metabolism enzyme key points drug metabolism typically results in the formation of a more hydrophilic compound that is readily excreted by the liver, kidney, andor gut. Specific chemical and fluorimetric methods were developed for the determination of the extracted isoniazid and acetylisoniazid, and chemical methods for the determination of. Furthermore, the metabolism in humans may be different from that in rats.
Perhaps the most important drug of all is isoniazid. Myeloperoxidase is likely the enzyme in the leukocyte involved. A solvent system was devised for the extraction of isoniazid and its metabolites acetylisoniazid, monoacetylhydrazine, diacetylhydrazine, isonicotinic acid and isonicotinylglycine from serum and urine. Abstract in this study, we aimed to quantify the effects of the nacetyltransferase 2 nat2 phenotype on isoniazid inh metabolism in vivo and identify other sources of pharmacokinetic variability following singledose administration in healthy asian adults. Trimodal frequency distributions for isoniazid inactivation were found in caucasian and negro populations. Psychotic re actions and coordination difficulties may result with disulfiram. It may also be used to treat mycobacterium avium complex, and mycobacterium kansasii. Myeloperoxidase is likely the enzyme in the leukocyte involved, since the oxidation was inhibited by azide, which. Aluminum containing antacids may decrease absorption. Isoniazid, also known as isonicotinic acid hydrazide inh, is an antibiotic used for the. Clinical pharmacokinetics of isoniazid springerlink. Inh, rifampicin rif, pyrazinamide pza and ethambutol emb.
Resistance resistance to isoniazid occurs because of mutations in the katg, inha, kasa and ahpc genes. A physiologically based pharmacokinetic model of isoniazid and its. Methoxsalen may decrease the excretion rate of isoniazid which could result in a higher serum level. Dec, 2012 the pharmacokinetics of isoniazid in man are described. Pharmacokinetics of isoniazid in lowbirthweight and.
Pdf metabolism of isoniazid a molecular modeling analysis. Isoniazid inh is used for treatment of tuberculosis as part of. The role of metabolism in the hepatotoxicity of isoniazid. Pharmacokinetic study of isoniazid and rifampicin in.
Isoniazid is used as a firstline drug to treat tuberculosis infection. Additionally, the concurrent use of enflurane and isoniazid may increase the risk of hepatotoxicity. Therefore, theophylline plasma levels should be monitored. Thank you for your interest in spreading the word about the bmj. Isoniazid inh is highly effective for the management of tuberculosis. Assuming that elimination of isoniazid follows firstorder kinetics, the rate constant for elimination of isoniazid andthe halflife ofisoniazid werecalculated onthebasis oftheconcentrations at2, 3, 6, and8hin slow inactivators, and at 2, 3, and 6 h only in rapid inactivators as someofthemhadindeterminate concentrations aug 01, 2014 isoniazid metabolism can be further supported by the isolation of different metabolites from the serum and urine of individuals undergoing isoniazid treatment 7. The determination of isoniazid and its metabolites. Choline magnesium trisalicylate may decrease the excretion rate of isoniazid which could result in a higher serum level. Isoniazid is metabolized in the liver mainly by acetylation and dehydrazination. Isoniazid, a hydrazine compound, is metabolized through. Yousefa,g, zhang luyonga,b,d and jiang zhenzhoua,c,e abstract. To access the pharmacokinetic profile of rifampicin and isoniazid and metabolites of isoniazid viz.
Isoniazid is an antituberculous drug that is usually administered for nine to 12 months. Isoniazid metabolism and hepatotoxicity researchgate. Ethambutol emb, e is a medication primarily used to treat tuberculosis. Thesewere bimodal, suggesting that individuals belong to one of twoclasseseither rapid or slowinactivators. Oct 24, 2006 no drug is more suited to such an approach than isoniazid isonicotinic acid hydrazide, inh, 1 in fig.
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