rifampin and acetylhydrazine

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

After i.v. and i.p. injections of isoniazid (Iso) 40 mg.kg-1 to male Wistar rats, the plasma levels of Iso, acetylisoniazid (AcIso), and acetylhydrazine (AcHz) were determined by spectrophotometric method and gas chromatography. The results suggested that the pharmacokinetic behavior of Iso in rats belonged to a 2-compartment model. The plasma levels of AcHz in rifampicin (Rif 30 mg.kg-1)-pretreated rats were lowered vs the control (P < 0.05 or < 0.01). The T1/2 of AcHz was shortened by Rif (control group 3.3 h, Rif-pretreated group 1.4 h) after i.v. injection of AcHz 10 mg.kg-1 to rats and the results showed that AcHz was converted to its active metabolites quickly by increasing the oxidative elimination rate of AcHz, which is related to the higher incidence of liver necrosis caused by Iso and Rif in combination.

Topics: Animals; Chemical and Drug Induced Liver Injury; Drug Interactions; Hydrazines; Isoniazid; Male; Rats; Rats, Wistar; Rifampin

It has been proposed that isoniazid-induced hepatotoxicity may be increased by concomitant rifampicin treatment and that this could be mediated by inducing the metabolism of the isoniazid metabolite monoacetylhydrazine to potent acylating agents capable of causing liver necrosis. To investigate this postulated mechanism we studied the kinetics of the metabolism of acetylisoniazid in a slow and a rapid acetylator prior to and after rifampicin administration. Pretreatment with rifampicin did not modify the metabolism of acetylisoniazid to any noteworthy extent nor did it increase the metabolism by non-acetylation routes of the monoacetylhydrazine liberated in vivo from acetylisoniazid.

Topics: Acetylation; Adult; Carcinogens; Humans; Hydrazines; Isoniazid; Liver; Male; Rifampin

The effect of rifampicin on the metabolism of isoniazid in human volunteer subjects has been investigated. The urinary metabolites of isoniazid after a single dose and after six daily doses of isoniazid plus rifampicin were examined. The isoniazid-rifampicin combination clearly increased the ratio of urinary 6-beta-hydroxycortisol to 17-hydroxycorticosteroids, indicating that induction of the microsomal enzymes had occurred. However, no significant changes in the urinary metabolites of isoniazid were detected, and therefore it is not possible to predict the effect of rifampicin on isoniazid hepatotoxicity.

Topics: 17-Hydroxycorticosteroids; Acetylation; Adult; Biotransformation; Creatinine; Humans; Hydrazines; Hydrocortisone; Isoniazid; Liver Function Tests; Male; Phenotype; Rifampin

Topics: Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Hydrazines; Isoniazid; Liver; Male; Phenobarbital; Rats; Rats, Inbred Strains; Rifampin