rifampin has been researched along with hydrazine* in 9 studies
9 other study(ies) available for rifampin and hydrazine
Article | Year |
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The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis.
In a mouse model, rifampicin and isoniazid combination treatment results in cholestatic liver injury that is associated with an increase in protoporphyrin IX, the penultimate heme precursor. Both ferrochelatase (FECH/Fech) and aminolevulinic acid synthase 1 (ALAS1/Alas1) are crucial enzymes in regulating heme biosynthesis. Isoniazid has recently been reported to upregulate Alas1 but downregulate Fech protein levels in mice; however, the mechanism by which isoniazid mediates disruption of heme synthesis has been unclear. Two metabolites of isoniazid, pyridoxal isonicotinoyl hydrazone (PIH, the isoniazid-vitamin B6 conjugate) and hydrazine, have been detected in the urine of humans treated with isoniazid. Here we show that, in primary human hepatocytes and the human hepatocellular carcinoma cell line HepG2/C3A, (1) isoniazid treatment increases Alas1 protein levels but decreases Fech levels; (2) hydrazine treatment upregulates Alas1 protein and Alas1 mRNA levels; (3) PIH treatment decreases Fech protein levels, but not Fech mRNA levels; and (4) PIH is detected after isoniazid treatment, with levels increasing further when exogenous vitamin B6 analogs are coadministered. In addition, the PIH-mediated downregulation of human FECH is associated with iron chelation. Together, these data demonstrate that hydrazine upregulates ALAS1, whereas PIH downregulates FECH, suggesting that the metabolites of isoniazid mediate its disruption of heme biosynthesis by contributing to protoporphyrin IX accumulation. Topics: 5-Aminolevulinate Synthetase; Animals; Carcinoma, Hepatocellular; Ferrochelatase; Heme; Hep G2 Cells; Hepatocytes; Humans; Hydrazines; Iron; Isoniazid; Liver; Mice, Inbred C57BL; Mice, Transgenic; Protoporphyrins; Pyridoxal; Rifampin; Vitamin B 6 | 2019 |
Design, synthesis and molecular docking of substituted 3-hydrazinyl-3-oxo-propanamides as anti-tubercular agents.
Based on the anti-mycobacterial activity of various acid hydrazides, a series of substituted 3-hydrazinyl-3-oxo-propanamides has been designed. The target compounds have been synthesized from diethylmalonate using substituted amines and hydrazine hydrate in ethanol. Computational studies and anti-tubercular activity screenings were undertaken to test their inhibitory effect on protein kinase PknB from Mycobacterium tuberculosis. Binding poses of the compounds were energetically favorable and showed good interactions with active site residues. Designed molecules obey the Lipinski's rule of 5 and gave moderate to good drug likeness score. Among the sixteen compounds (1-16) taken for in silico and in vitro studies, 3 compounds (11, 12 and 15) have shown good binding energies along with exhibiting good anti-tubercular activity and thus may be considered as a good inhibitors of PknB. Topics: Amides; Antitubercular Agents; Binding Sites; Drug Design; Humans; Hydrazines; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Protein Structure, Secondary; Protein Structure, Tertiary | 2014 |
Synthesis, anti-tubercular activity and 3D-QSAR study of coumarin-4-acetic acid benzylidene hydrazides.
A set of 25 coumarin-4-acetic acid benzylidene hydrazides were synthesized and characterized by NMR, IR and mass spectroscopic techniques. The compounds were evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H(37)Rv strain using the BACTEC 460 system to determine percentage inhibition. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by Comparative Molecular Field Analysis (CoMFA). Several statistically significant CoMFA models were generated. The CoMFA model generated with database alignment was the best in terms of overall statistics. The CoMFA contours provide a good insight into the structure activity relationships of the compounds reported herein. Topics: Acetic Acid; Antitubercular Agents; Benzaldehydes; Coumarins; Hydrazines; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Quantitative Structure-Activity Relationship | 2008 |
Isoniazid and its toxic metabolite hydrazine induce in vitro pyrazinamide toxicity.
Antituberculosis drug-induced hepatotoxicity (ATDH) complicates the treatment of 5-10% of patients treated for active tuberculosis (TB). Knowledge regarding the mechanism of toxicity is still incomplete. Metabolism and the formation of toxic metabolites of the TB drugs may play an important role in the development of ATDH. We studied hepatotoxicity and interactions between isoniazid (INH), its toxic metabolite hydrazine (HYD), rifampicin (RIF) and pyrazinamide (PZA) in human hepatoma cells (HepG2). After 24h pre-treatment with a non-toxic concentration of one of the four compounds, cells were exposed to increasing concentrations of INH, HYD, RIF or PZA. To determine whether pre-treatment increased toxicity, changes in the concentration at which 50% of cell growth was inhibited (IC50) were quantified using the WST-1 cytotoxicity assay. Pre-treatment with INH, HYD or RIF decreased the INH IC50 by 24%, 26% and 15%, respectively, meaning that INH toxicity was increased. INH and HYD pre-treatment decreased the PZA IC50 by 30% and 38%, respectively. HYD and RIF toxicity were not affected by the pre-treatments. The present study is the first to demonstrate that pre-treatment with INH or its toxic metabolite HYD increases the in vitro toxicity of PZA. In addition, pre-treatment with INH, HYD or RIF increases the in vitro toxicity of INH. These results give us greater insight into the development of ATDH. Topics: Antitubercular Agents; Cell Line, Tumor; Cell Survival; Chemical and Drug Induced Liver Injury; Humans; Hydrazines; Isoniazid; Liver; Pyrazinamide; Rifampin | 2008 |
The effect of pyrazinamide and rifampicin on isoniazid metabolism in rats.
Hepatotoxicity is the main concern during tuberculosis chemotherapy with the first-line drugs isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR). Since these hepatotoxic events have been associated with INH metabolites, the study aimed to measure the area under curve (AUC) parameter for INH and its metabolites acetylisoniazid (AcINH), hydrazine (Hz) and acetylhydrazine (AcHz), when groups of rats were pre-treated for 21 days with INH alone or in combination with RMP and/or PYR, in the following amounts per kg body weight: INH 100 mg; INH 100 mg + RMP 100 mg; INH 100 mg + PYR 350 mg; INH 100 mg + PYR 350 mg + RMP 100 mg. It was found that co-administration of RMP, PYR and RMP + PYR caused a significant decrease in the AUC for INH. Co-administration of PYR was the only treatment that caused a significant increase in the AUC for Hz and a decrease in the AUC for its acetylated product AcHz. The AUC for AcINH was not significantly altered in any experimental group. In conclusion, the increased metabolism of INH in all the drug combinations and the significantly higher production of Hz in the group INH + PYR might be linked with exacerbated hepatotoxic effects of these drug associations. Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Area Under Curve; Biological Availability; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Hydrazines; Intubation, Gastrointestinal; Isoniazid; Male; Pyrazinamide; Rats; Rats, Wistar; Rifampin; Time Factors | 2007 |
CYP2E1 mediated isoniazid-induced hepatotoxicity in rats.
To investigate the role of CYP2E1 in isoniazid (INH)-induced hepatotoxicity and the influence of rifampicin (RFP) on INH-induced liver injury.. Rats were treated with INH alone (100 mg/kg, ip) or co-administered with RFP (100 mg/kg, ig) for 10 d and 21 d. Hepatotoxicity was assayed by plasma enzymes (sALT, sAST) and histopathological examinations. Hepatic CYP2E1 activity was measured by aniline hydroxylase (ANH), and CYP2E1 mRNA expression was determined by RT-PCR. Plasma hydrazine concentration was determined by RP-HPLC.. For a 10 d INH-treatment, hepatic CYP2E1 level was increased to 3.7-fold over the control; liver impairment appeared after 21 d treatment, while CYP2E1 and plasma hydrazine were, respectively, increased to 4.6-fold and 1.7-fold. However, in INH-RFP group for 10 d, CYP2E1 and plasma hydrazine were, respectively, decreased by 13 % and 18 % over INH group; similarly, hepatic injury is equal to INH group appeared after 21 d, and CYP2E1 was further decreased by 26 %. Correlation analysis showed that sALT had a positive correlation with plasma hydrazine and with CYP2E1 activity; CYP2E1 activity was also markedly correlated with plasma hydrazine. And compared with control, there is no difference in changes of CYP2E1 mRNA expression in INH and INH-RFP treatment for 21 d.. The metabolite of INH, hydrazine, plays an important role in INH-induced hepatotoxicity in rats. The induction of CYP2E1 by hydrazine is involved in the hepatotoxicity of INH. RFP does not exacerbate INH-induced hepatotoxicity in short term, which relates to down-regulation of CYP2E1. Topics: Alanine Transaminase; Animals; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Down-Regulation; Hydrazines; Isoniazid; Liver; Male; Rats; Rifampin; RNA, Messenger | 2004 |
[Persistent fever syndrome in a case of childhood tuberculosis].
Topics: Child, Preschool; Fever; Fever of Unknown Origin; Humans; Hydrazines; Male; Pyrazinamide; Rifampin; Tuberculosis, Miliary; Tuberculosis, Pulmonary | 1991 |
Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin.
The effect of daily administration of rifampin on the direct conversion of isoniazid to isonicotinic acid and hydrazine by isoniazid hydrolase was investigated in 6 slow and 8 rapid acetylators of isoniazid. The proportion of isoniazid metabolized through this direct pathway during the first 6 h was estimated from the ratio of total isonicotinic acid formed to acetylisoniazid in urine after administration of isoniazid or acetylisoniazid. In slow acetylators, this proportion was approximately 3% when isoniazid alone was administered and approximately 6% during the maximal phase of induction caused by the daily administration of rifampin in addition to isoniazid (p less than 0.001); in rapid acetylators, the proportions were considerably less (less than 1 and 2.5%, respectively), suggesting that isoniazid hydrolase was induced by rifampin. The increased formation of hydrazine, a known hepatotoxic agent in animals, could explain the substantially higher frequency of the occurrence of hepatitis in slow than in rapid acetylators among tuberculous patients treated with daily rifampin and isoniazid. Topics: Acetylation; Chemical and Drug Induced Liver Injury; Drug Combinations; Humans; Hydrazines; Isoniazid; Rifampin; Tuberculosis | 1986 |
Effects of rifampicin and phenobarbital on the fate of isoniazid and hydrazine in vivo in rats.
After the intraperitoneal (i.p.) administration of isoniazid (INH) to male Wistar rats, the liver and plasma levels of hydrazine (Hz) and acetylhydrazine (AcHz), which are hazardous metabolites of INH and well known as mutagens, carcinogens and hepatotoxins, were determined by gas chromatography-mass spectrometry (GC-MS). The levels of Hz in rifampicin (RMP)- or phenobarbital (PB)-pretreated groups were lower than those in the control group, while the amount of AcHz was scarcely altered. In each of the pretreated groups a pronounced increase in the oxidative elimination rate of Hz was observed. These results are of important toxicological significance in INH therapy with RMP, since an active intermediate of Hz seems to be a hepatotoxin. Topics: Acetylation; Animals; Drug Interactions; Hydrazines; Isoniazid; Liver; Male; Oxidation-Reduction; Phenobarbital; Rats; Rats, Inbred Strains; Rifampin | 1985 |