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Identification of Metoprolol Tartrate-Derived Reactive Metabolites Possibly Correlated with Its Cytotoxicity

Xiaonan Li1, Gang Xing2, Xinxin Guo1

  • 1Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, P. R. China.

Chemical Research in Toxicology
|May 16, 2022
PubMed

Insights

Metoprolol tartrate (MTA) can cause liver injury through reactive metabolites. This study identified these metabolites and a potential quinone methide intermediate, linking metabolic activation to MTA

Area of Science:

  • Pharmacology
  • Hepatology
  • Drug Metabolism

Background:

  • Metoprolol tartrate (MTA) is a selective β1-receptor antagonist used for cardiovascular diseases.
  • Hepatotoxicity from MTA has been reported, but the underlying mechanism remains unclear.

Purpose of the Study:

  • Identify reactive metabolites of MTA.
  • Determine the metabolic activation pathway of MTA.
  • Correlate MTA's metabolic activation with its cytotoxicity.

Main Methods:

  • Rat liver microsomal incubations with MTA, glutathione (GSH), and N-acetyl cysteine (NAC).
  • Detection of metabolites in hepatocytes, bile, and urine.
  • Assessment of MTA-induced cytotoxicity in cultured rat primary hepatocytes.
  • Use of a P450 enzyme inhibitor (aminobenzotriazole).

Main Results:

  • Three oxidative metabolites (M1-M3), a GSH conjugate (M4), and an NAC conjugate (M5) were identified.
  • M4 was found in hepatocytes and bile; M5 was found in urine.
  • A reactive quinone methide intermediate was proposed.
  • MTA induced significant cytotoxicity in hepatocytes, which was reduced by P450 inhibition.

Conclusions:

  • MTA undergoes metabolic activation to reactive intermediates.
  • These reactive metabolites are linked to MTA's cytotoxicity.
  • Understanding this mechanism may help predict or prevent MTA-induced liver injury.

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