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In vitro studies on the metabolic fate of mifentidine, a novel histamine H2-receptor antagonist

K Pattichis1, M Kajbaf, J W Gorrod

  • 1Chelsea Department of Pharmacy, King's College London, University of London, UK.

European Journal of Drug Metabolism and Pharmacokinetics
|April 1, 1997
PubMed

Insights

This study investigated the in vitro metabolism of mifentidine in animal hepatic microsomes, identifying key metabolites like 4-imidazolylphenylamine and formamide. Cytochromes P450I and P450II were implicated in mifentidine

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Biochemistry

Background:

  • Mifentidine is a drug requiring understanding of its metabolic pathways.
  • In vitro studies are crucial for elucidating drug biotransformation.
  • Animal models provide insights into xenobiotic metabolism.

Purpose of the Study:

  • To characterize the in vitro metabolism of mifentidine.
  • To identify mifentidine metabolites and their postulated intermediates.
  • To investigate the role of specific enzyme systems in mifentidine biotransformation.

Main Methods:

  • Incubation of mifentidine with hepatic microsomes from seven animal species.
  • Analysis of metabolites using High-Performance Liquid Chromatography (HPLC), UV spectroscopy, and Mass Spectrometry (MS).
  • Investigation of enzyme inducers, inhibitors, and activators.

Main Results:

  • Identification of four major mifentidine metabolites: 4-imidazolylphenylamine (amine), 4-imidazolylphenyl-formamide (formamide), urea derivative (urea), and imidazole-hydroxylated amine (i-OH-amine).
  • Postulation of metabolic intermediates including carbinolimine, formamide, amine, and nitrone.
  • Identification of a unique metabonate: the nitro analogue of the amine.
  • Demonstration of Cytochromes P450I and P450II involvement in mifentidine metabolism.
  • Inconclusive evidence for flavin monooxygenase system involvement.

Conclusions:

  • Mifentidine undergoes extensive in vitro metabolism in animal hepatic microsomes.
  • Cytochromes P450I and P450II are key enzymes in mifentidine biotransformation.
  • Further studies are needed to confirm the role of other enzyme systems and to fully elucidate the metabolic pathways.

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