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Metabolism of tocainide in the rat
Abstract:
The metabolism of tocainide, an oral antiarrhythmic agent, was studied in male Wistar rats following oral administration of 15 mg/kg of tocainide hydrochloride. Qualitative and quantitative identification of the metabolites in urine was carried out by GC-mass spectrometry and electron capture detector gas chromatography. About 15-20% of the dose administered was excreted as intact drug in the urine. An additional 20% of the dose was present as acid hydrolysable conjugates. Enzymatic hydrolysis (beta-glucuronidase) revealed half of the acid hydrolysable conjugates to be a glucuronide. The enzyme mediated hydrolysis was blocked by its specific inhibitor saccharo-1,4-lactone. N-acetyl tocainide, an oxidatively deaminated tocainide, an aldehyde adduct of tocainide, and a cyclic hydantoin derivative of tocainide were also identified as metabolites in the urine samples.
Insights
Tocainide metabolism in rats revealed significant urinary excretion of intact drug and various metabolites. Key findings include glucuronide conjugates and novel derivatives like N-acetyl tocainide.
Area of Science:
- Pharmacology
- Drug Metabolism
- Toxicology
Background:
- Tocainide is an oral antiarrhythmic agent.
- Understanding its metabolic pathways is crucial for therapeutic efficacy and safety.
Purpose of the Study:
- To elucidate the metabolic fate of tocainide in vivo.
- To identify and quantify tocainide metabolites in rat urine.
Main Methods:
- Oral administration of tocainide hydrochloride to male Wistar rats.
- Urine sample analysis using GC-mass spectrometry and electron capture detector gas chromatography.
- Enzymatic hydrolysis with beta-glucuronidase and chemical hydrolysis to identify conjugates.
Main Results:
- 15-20% of the administered tocainide dose was excreted unchanged in urine.
- Approximately 20% of the dose was excreted as acid-hydrolyzable conjugates, with half identified as glucuronides.
- Metabolites identified include N-acetyl tocainide, oxidatively deaminated tocainide, an aldehyde adduct, and a cyclic hydantoin derivative.
Conclusions:
- Tocainide undergoes extensive metabolism in rats.
- Multiple metabolic pathways contribute to tocainide excretion, including conjugation and oxidative transformations.
- The identification of novel metabolites provides insights into tocainide's pharmacokinetic profile.