Co-administration Of Isoniazid Research Articles

Catechin ameliorates hepatocellular damage caused by coadministration of isoniazid and rifampicin

It is well known that phyto-constituents possess hepatoprotective properties. The radical scavenging potential of catechin has received substantial research. The goal of the current study was to assess the beneficial effect of Catechin to safeguard rats from liver damage caused by isoniazid and rifampicin. In this investigation, Wistar rats were employed. Administration of isoniazid (100 mg/kg) with rifampicin (100 mg/kg) for 21 days caused hepatocellular injury. The dosages of catechin used were 25, 50, and 100 mg/kg body weight. Blood was drawn at the end of the study, and biochemical tests were performed to determine the enzyme levels. Restoration of AST, ALT, and ALP was brought about by catechin administration (25, 50, and 100 mg/kg body weight). The administration lead to in a restoration of the SOD and catalase levels. The expression of TNF-α, IL-1β, IL-6, MDA, and nitric oxide decreased. The findings prove that catechin had a significant hepatoprotective impact. The hepatoprotective action of catechin might be mediated by the radical scavenging and cytokine suppressing effects.

The identification of key metabolites and mechanisms during isoniazid/rifampicin-induced neurotoxicity and hepatotoxicity in a mouse model by HPLC-TOF/MS-based untargeted urine metabolomics

The co-administration of isoniazid (INH) and rifampicin (RIF) is associated with hepatotoxicity and neurotoxicity. To systematically investigate the mechanisms of hepatotoxicity and neurotoxicity induced by INH/RIF, we used high performance liquid chromatography-time of flight mass spectrometry (HPLC-TOF/MS)-based untargeted metabolomics to analyze urine from a mouse model and screened a range of urinary biomarkers. Mice were orally co-administered with INH (120 mg/kg) and RIF (240 mg/kg) and urine samples were collected on days 0, 7, 14 and 21. Hepatotoxicity and neurotoxicity were assessed by samples of liver, brain and kidney tissue which were harvested for histological analysis. Toxicity analysis revealed that INH/RIF caused hepatotoxicity and neurotoxicity in a time-dependent manner; compared with day 0, the levels of 35, 82 and 86 urinary metabolites were significantly different on days 7, 14 and 21, respectively. Analysis showed that by day 21, exposure to INH+RIF had caused disruption in vitamin B6 metabolism; the biosynthesis of unsaturated fatty acids; tyrosine, taurine, hypotaurine metabolism; the synthesis of ubiquinone and other terpenoid-quinones; and the metabolism of tryptophan, nicotinate and nicotinamide. Nicotinic acid, nicotinuric acid and kynurenic acid were identified as sensitive urinary biomarkers that may be useful for the diagnosis and evaluation of toxicity.

Pharmacokinetic Assessment of Pyrazinamide and Pyrazinoic Acid in Carbon tetrachloride-induced Liver Injury Model in Wistar Rats.

We investigated the pharmacokinetic behavior of pyrazinamide (PZA) and pyrazinoic acid (PA) in the presence of carbon-tetrachloride (CCl4) plus antitubercular treatment (ATT) drug-induced liver injury (DILI) in rats. Thirty rats utilized in the experiment were separated equally into five groups. Each rat was injected with 0.5 ml/kg CCl4 intra-peritoneal injection on day zero. Group, I rats did receive only CCl4 (single i.p. injection, 0.5 ml/Kg in olive oil in a 1:1 ratio). Groups II, III, IV, and V did receive daily oral PZA, PZA plus isoniazid (INH), rifampicin (RMP) plus pyrazinamide (PZA), and three drugs together, respectively, for 21-days. Pharmacokinetic sampling was performed at 0, 0.5,1,3,6,12 and 24 hours post-dosing on day-20. Liver function test (LFT) was assessed at days 0,1,7, and 21 days after CCl4 and ATT administration, and rats were sacrificed on the last experiment day. ATT treatment maintained the liver function changes initiated by CCl4 administration. An evidential LFT rise was observed in groups administered with pyrazinamide. Co-administration of Isoniazid caused a 2.02 and 1.78 times increase in Area-under-the-curve (AUC) values of PZA and PA, respectively (p < 0.05). Histological and oxidative-stress changes supported the biochemical and pharmacokinetic observations. The enzyme inhibitory capacity of isoniazid is well-preservd in CCl4-induced liver injury.

Exploration of the underlying mechanisms of isoniazid/rifampicin-induced liver injury in mice using an integrated proteomics and metabolomics approach.

The hepatotoxic mechanism resulting from coadministration of isoniazid (INH) and rifampicin (RIF) are complex and studies remain inconclusive. To systematically explore the underlying mechanisms, an integrated mass-based untargeted metabolomics and label-free quantitative proteomics approach was used to clarify the mechanism of INH/RIF-induced liver injury. Thirty male mice were randomly divided into three groups: control (receiving orally administered vehicle solution), INH (150 mg/kg) + RIF (300 mg/kg) orally administered for either 7or 14 days, respectively. Serum was collected for the analysis of biochemical parameters and liver samples were obtained for massspectrum-based proteomics, metabolomics, and lipidomics analysis. Overall, 511 proteins, 31 metabolites, and 23 lipids were dysregulated and identified, and disordered biological pathways were identified. The network of integrated multiomics showed that glucose, lipid, and amino acid metabolism as well as energy metabolism were mainly dysregulated and led to oxidative stress, inflammation, liver steatosis, and cell death induced by INH and RIF. Coadministration of INH and RIF can induce liver injury by oxidative stress, inflammation, liver steatosis, and cell death, and the reduction in glutathione levels may play a critical role in these systematic changes and warrants further study.

The protective effect of lycopene against oxidative kidney damage associated with combined use of isoniazid and rifampicin in rats.

It is known that the combined use of antibiotics, such as isoniazid and rifampicin, in the treatment of tuberculosis causes oxidative kidney damage. The aim of this study was to biochemically and histopathologically investigate the effect of lycopene on oxidative kidney damage due to the administration of isoniazid and rifampicin in albino Wistar male rats. Lycopene at a dose of 5 mg/kg was orally administered to lycopene+isoniazid+rifampicin (LIR) rats, and normal sunflower oil (0.5 mL) was orally administered to isoniazid+rifampicin (IR) and healthy control (HG) rats as vehicle by gavage. One hour after the administration of lycopene and vehicle, 50 mg/kg isoniazid and rifampicin were given orally to the LIR and IR groups. This procedure was performed once a day for 28 days. Rats were sacrificed by a high dose of anesthesia at the end of this period, and oxidant-antioxidant parameters were measured in the removed kidney tissues. Creatinine and blood urea nitrogen (BUN) levels were measured in blood samples, and kidney tissues were also evaluated histopathologically. The combined administration of isoniazid and rifampicin changed the oxidant-antioxidant balance in favor of oxidants, and it increased blood urea nitrogen and creatinine levels, which are indicators of kidney function. Co-administration of isoniazid and rifampicin also caused oxidative kidney damage. Lycopene biochemically and histopathologically decreased oxidative kidney damage induced by isoniazid and rifampicin administration. These results suggested that lycopene may be beneficial in the treatment of nephrotoxicity due to isoniazid and rifampicin administration.

Sagittaria sagittifolia polysaccharide protects against isoniazid- and rifampicin-induced hepatic injury via activation of nuclear factor E2-related factor 2 signaling in mice

Ethnopharmacological relevanceThe Sagittaria sagittifolia L. polysaccharide (SSP) is a purified form of a homogeneous polysaccharide isolated from the root tubers of S. sagittifolia, which has been used as a protectant against hepatotoxicity induced by coadministration of isoniazid and rifampicin. However, the protective effect of SSP against isoniazid- and rifampicin-induced liver injury has never been studied. Aim of the studyIn this study, the hepatoprotective effect of SSP and its underlying mechanism were investigated in mice with isoniazid- and rifampicin-induced liver injury. Materials and methodsLiver injury was induced in mice by intragastric administration of isoniazid and rifampicin, and the mice were divided into the following six groups: standard control (administration of saline by gavage), model (intragastric administration of isoniazid and rifampicin at 100 mg/kg/day each), positive control (100 mg/kg/day silymarin by gavage 4 h after isoniazid and rifampicin administration), and SSP-treated (200, 400, or 800 mg/kg/day SSP by gavage after isoniazid and rifampicin administration). Subsequently, blood and liver samples were collected from all the animals and were assessed. ResultsSSP significantly alleviated the liver injury, as evidenced by decreased activities of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase in the serum and a decreased level of malondialdehyde in the liver, as well as by an increased level of glutathione and increased activities of superoxide dismutase and catalase in the liver. SSP also effectively reduced the pathological tissue damage. The gene and protein expression of cytochrome P450 (CYP) 2E1 and CYP3A4 was inhibited by SSP. The gene and protein expression of nuclear factor erythroid 2-related factor 2 (NRF2), glutamate-cysteine ligase, and heme oxygenase-1 were induced by SSP, whereas that of Kelch-like ECH-associated protein 1 was inhibited. ConclusionsSSP exerts a protective effect against isoniazid- and rifampicin-induced liver injury in mice. The underlying mechanisms may involve activation of NRF2 and its target antioxidant enzymes and inhibition of the expression of CYPs.

The Alcohol Intolerance Produced by Isoniazid Is Not Due to a Disulfiram-Like Reaction Despite Aldehyde Dehydrogenase Inhibition

Background/Aims: Isoniazid (ISO) has been reported to inhibit the hepatic aldehyde dehydrogenase (ALDH) and to cause a disulfiram (DIS)-like reaction, albeit there are no reports demonstrating increased blood acetaldehyde levels after co-administration of ISO with alcohol. The aim of our study was to clarify whether the alcohol intolerance produced by ISO is indeed due to a typical DIS-like reaction. Methods: DIS and ISO were administered to Wistar rats and the hepatic ethanol (ETH) metabolizing enzyme activities along with the levels of brain monoamines were determined. Blood acetaldehyde levels were also evaluated after co-administration of ETH with DIS or ISO. Results: Despite inhibition of the hepatic ALDH, ISO did not result in elevated blood acetaldehyde levels after ETH administration, probably due to the induction of cytochrome P450 2E1 which theoretically leads to an increased elimination rate of acetaldehyde preventing its accumulation. Moreover, ISO produced some minor, but statistically significant, alterations in central monoaminergic neurotransmission. Conclusion: Our results demonstrate for the first time that despite ALDH inhibition ISO does not provoke a typical DIS-like reaction since it does not increase blood acetaldehyde levels after co-administration with ETH. The possibility that the ETH intolerance observed in ISO treatment is a central synergistic effect cannot be excluded.

Chemotherapeutic activity against murine tuberculosis of once weekly administered drugs (isoniazid and rifampicin) encapsulated in liposomes

Co-administration of isoniazid (INH) and rifampicin (RIF) encapsulated in lung specific stealth liposomes at one third of their recommended doses of 12 and 10 mg/kg b.wt., respectively, exhibited a sustained release of these drugs in plasma (5 days) and lungs, liver and spleen (7 days). At these concentrations, T max and area under curve (AUC) values of liposomal drugs were more than that observed with free drugs. The elimination constant (Kel) was higher for liposomal INH (−0.034±0.008) and RIF (−0.017±0.009) compared with free INH (−0.392) and RIF (−0.243). Chemotherapeutic efficacy of once weekly-administered liposomal drugs for 6 weeks reduced the mycobacterial load significantly in lungs, liver and spleen of infected mice compared with untreated animals.

Isoniazid is a mechanism-based inhibitor of cytochrome P 450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes

In order to evaluate the inhibitory effects of isoniazid on cytochrome P450 (CYP) mediated drug metabolism, the in vitro inhibitory potency and specificity as well as the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-, time- and concentration dependency of isoniazid as an inhibitor of the activity of the major human CYP isoforms were studied. Using pooled human liver microsomes, the in vitro inhibitory effects of isoniazid on CYP1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (tolbutamide hydroxylation), CYP2CI9 (S-mephenytoin 4'-hydroxylation), CYP2D6 (dextromethorphan O-demethylation), CYP2E1 (chlorzoxazone 6-hydroxylation) and CYP3A4 (midazolam 1'-hydroxylation) activities were examined. After a 15-min preincubation without NADPH, isoniazid reversibly inhibited microsomal CYP2C19- and CYP3A4-mediated reactions with apparent Ki values of 36 microM and 73 microM, respectively. However, isoniazid had only weak inhibitory effects on the five other CYP-mediated reactions (Ki > 110 microM). After a 15-min preincubation with NADPH, isoniazid showed an increased inhibitory potency toward CYP1A2, CYP2A6, CYP2C19 and CYP3A4 activities (Ki = 56, 60, 10 and 36 microM, respectively). In addition, the inactivation of CYP1A2, CYP2A6, CYP2C19 and CYP3A4 by isoniazid was NADPH-, time- and concentration dependent, and was characterised by Kinact values of 0.11, 0.13, 0.09 and 0.08 min(-1), and K1 values of 285, 173, 112 and 228 microM, respectively. As the peak plasma concentrations of isoniazid are around 30-50 microM, isoniazid at clinically relevant concentrations reversibly inhibits CYP2C19 and CYP3A4 activities, and mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 and CYP3A4 in human liver microsomes. Co-administration of isoniazid and drugs that are primarily metabolised by these CYP isoforms, particularly by CYP2C19 and CYP3A4, may result in significant drug interactions.

Suppression of deferoxamine mesylate treatment — induced side effects by coadministration of isoniazid in a patient with Alzheimer's disease subject to aluminum removal by ionspecific chelation

Deferoxamine treatment may produce serious side effects that can be eliminated by modification of treatment and by control of deferoxamine metabolism. A patient suffering from dementia of the Alzheimer type with normal liver and kidney function who was treated with deferoxamine initially tolerated a dose of 7 mg/kg deferoxamine mesylate injected intramuscularly twice a day for a total of 5 days a week. After several months nausea and weight loss gradually developed in the patient that could be controlled initially by dose reduction, leading to levels inappropriate for aluminum chelation. HPLC analysis of blood and urine revealed several metabolites including, as a major component, a plasma monoamine oxidase (MAO) catalyzed end product MFO1. Coadministration of isoniazid, a plasma MAO inhibitor, with deferoxamine resulted in reduction of MFO1 from 81% to 8% accompanied by increases in the amounts of metabolite 2 (MFO2) from 2% to 24% and unmetabolized deferoxamine from 17% to 68% after 6 months of treatment. The side effects subsided, the patient regained weight, and treatment could be continued.

Differential effects of isoniazid and oral contraceptive steroids on antipyrine oxidation and acetaminophen conjugation.

Factors influencing hepatic oxidation of antipyrine and conjugation of acetaminophen were evaluated in volunteers who received 1.0 g of antipyrine intravenously and on a different occasion a 650 mg intravenous dose of acetaminophen. In study one, subjects received both drugs in the control state and at another time during coadministration of isoniazid (INH), 180 mg daily. In control versus INH conditions, mean clearance of antipyrine was reduced from 0.67 to 0.60 ml/min/kg as was clearance of acetaminophen from 4.97 to 4.23 ml/min/kg, but these differences were not statistically significant. In study two, females on low-dose estrogen oral contraceptives (OC) and drug-free controls matched for age received both drugs. Compared to controls, OC users had reduced total clearance of antipyrine (0.71 vs. 0.50 ml/min/kg; p less than 0.005) and prolonged antipyrine t1/2 (9.6 vs. 13.3 h; p less than 0.005). For acetaminophen, however, OC users had higher clearance (5.2 vs. 6.1 ml/min/kg) and shorter t1/2 (2.2 vs. 1.9 h) although differences did not attain statistical significance. Clearance of antipyrine and acetaminophen across both studies was not statistically significantly correlated within individuals (r = 0.22). The capacities for drug oxidation and conjugation appear to be controlled by different mechanisms.

Differential effect of isoniazid on triazolam oxidation and oxazepam conjugation.

Healthy volunteers received a single dose of triazolam (0.5 mg) or oxazepam (30 mg) on two occasions, once in the control state and again during coadministration of isoniazid (INH) base, 180 mg day. INH coadministration prolonged triazolam half-life (3.3 vs 2.5 h, P less than 0.05) and increased total area under the curve (38.6 vs 26.5 ng ml-1 h, P less than 0.01) consistent with a reduction of apparent oral clearance (3.9 vs 6.8 ml min-1 kg-1, 0.05 less than P less than 0.1). INH coadministration had no influence on the kinetics of oxazepam. INH impairs hepatic microsomal oxidation of triazolam, leading to reduced first-pass hepatic extraction as well as prolonged half-life. However INH had no influence on oxazepam conjugation.