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Is isoniazid-hepatotoxicity induced by the metabolite, hydrazine?
Abstract:
The effects of rifampicin (RMP) on isoniazid (INH) metabolism in rabbits were examined from the viewpoint of extensive hepatitis. After the RMP pretreatment, no remarkable changes were observed in the plasma levels of INH as well as its metabolites, acetylisoniazid (AcINH), acetylhydrazine (AcHz) and diacetylhydrazine (DAcHz) with the exception of hydrazine (Hz). After an oral administration of INH or Hz hydrate, the stochastic examination showed that the AUC0-8hr values of Hz plasma levels in RMP pretreated groups were significantly less than those in the control rabbits. RMP treatment was also shown to induce rabbit liver cytochrome P-450 activity. Histological studies demonstrated that Hz causes more remarkable hepatic necrosis in rabbits pretreated with RMP than in the control rabbits. These observations could suggest that Hz is a key intermediate of INH-hepatitis through the transformation of some hepatotoxic species by microsomal oxidation that is facilitated by RMP.
Insights
Rifampicin (RMP) pretreatment alters isoniazid (INH) metabolism, increasing hydrazine (Hz) toxicity. This suggests hydrazine is a key intermediate in drug-induced hepatitis, exacerbated by RMP-induced liver enzyme activity.
Area of Science:
- Pharmacology
- Hepatology
- Drug Metabolism
Background:
- Isoniazid (INH) is a primary anti-tuberculosis drug.
- Drug-induced liver injury, particularly hepatitis, is a significant concern with INH therapy.
- Rifampicin (RMP) is often co-administered with INH, necessitating understanding of their interactions.
Purpose of the Study:
- To investigate the impact of rifampicin (RMP) on isoniazid (INH) metabolism in rabbits.
- To elucidate the role of hydrazine (Hz) as a potential mediator of INH-induced hepatitis.
- To examine the influence of RMP on liver enzyme activity and its subsequent effect on drug toxicity.
Main Methods:
- Rabbits were pretreated with RMP before INH or Hz administration.
- Plasma levels of INH and its metabolites (AcINH, AcHz, DAcHz, Hz) were quantified.
- Area Under the Curve (AUC) for Hz plasma levels was calculated.
- Rabbit liver cytochrome P-450 activity was assessed.
- Histological examination of liver tissue was performed to evaluate hepatic necrosis.
Main Results:
- RMP pretreatment did not significantly alter plasma levels of INH, AcINH, AcHz, or DAcHz.
- A notable exception was hydrazine (Hz), whose plasma levels showed complex changes.
- AUC0-8hr values for Hz were significantly lower in RMP-pretreated rabbits.
- RMP administration induced rabbit liver cytochrome P-450 activity.
- Histological studies revealed more pronounced hepatic necrosis induced by Hz in RMP-pretreated rabbits.
Conclusions:
- Hydrazine (Hz) appears to be a critical intermediate in the development of INH-induced hepatitis.
- RMP-induced enhancement of microsomal oxidation facilitates the transformation of Hz into hepatotoxic species.
- These findings highlight a potential mechanism for RMP exacerbating INH hepatotoxicity.