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Metabolism of roxithromycin in the isolated perfused rat liver
K Jarukamjorn1, T Thalhammer, B Gollackner
1Institute of Pharmaceutical Chemistry, University of Vienna, Austria.
Abstract:
Roxithromycin is a macrolide antibiotic with high clinical potency. N-Demethylation is considered to be one of the main pathways of roxithromycin metabolism in rats. We have studied the hepatic metabolism of roxithromycin in the isolated perfused rat liver. After addition of roxithromycin (30 microM) to the perfusion medium the parent compound and one major metabolite were detected in bile by high-performance liquid chromatography. The metabolite was identified as monodesmethylated roxithromycin by mass spectrometric analysis. Onset of biliary excretion of native roxithromycin was fast, reaching a maximum (130.52 +/- 43.88 pmol g(-1) min(-1)) after only 10 min, whereas excretion of the metabolite was delayed (maximum 75.83 +/- 11.92 pmol g(-1) min(-1) at 30 min). The cumulative excretion of roxithromycin and its metabolite into bile during the 60 min of application amounted to only 1.09 +/- 0.30 and 0.64 +/- 0.22% of the roxithromycin cleared from the perfusate during the same time. The liver content was 0.48 micromol (g liver)(-1), indicating high retention within the organ. No release of the metabolite into the perfusate was detected. In conclusion, this study has demonstrated the importance of phase-I metabolism for the biliary excretion of roxithromycin in rat liver. These findings might be predictive of roxithromycin biotransformation and biliary excretion in man.
Insights
This study investigated roxithromycin metabolism in isolated rat livers. Phase-I metabolism, specifically N-demethylation, is crucial for the biliary excretion of this potent macrolide antibiotic.
Area of Science:
- Pharmacology
- Hepatology
- Drug Metabolism
Background:
- Roxithromycin is a potent macrolide antibiotic used clinically.
- N-demethylation is a primary metabolic pathway for roxithromycin in rats.
- Understanding hepatic metabolism is key to predicting drug excretion.
Purpose of the Study:
- To investigate the hepatic metabolism and biliary excretion of roxithromycin in an isolated perfused rat liver model.
- To identify and quantify roxithromycin and its metabolites in bile.
- To assess the role of Phase-I metabolism in roxithromycin's excretion.
Main Methods:
- Isolated perfused rat liver model.
- High-performance liquid chromatography (HPLC) for compound detection.
- Mass spectrometry for metabolite identification.
Main Results:
- Monodesmethylated roxithromycin was identified as a major metabolite in bile.
- Biliary excretion of native roxithromycin was rapid, while metabolite excretion was delayed.
- Low cumulative excretion into bile (<2%) and high liver retention were observed.
- No metabolite was detected in the perfusate.
Conclusions:
- Phase-I metabolism significantly influences the biliary excretion of roxithromycin in rat liver.
- The findings suggest potential implications for roxithromycin biotransformation and biliary excretion in humans.
