Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine

Br J Clin Pharmacol. 2001 Feb;51(2):133-42. doi: 10.1111/j.1365-2125.2001.01292.x.


Aims: The aims of the present study were to investigate the metabolism of astemizole in human liver microsomes, to assess possible pharmacokinetic drug-interactions with astemizole and to compare its metabolism with terfenadine, a typical H1 receptor antagonist known to be metabolized predominantly by CYP3A4.

Methods: Astemizole or terfenadine were incubated with human liver microsomes or recombinant cytochromes P450 in the absence or presence of chemical inhibitors and antibodies.

Results: Troleandomycin, a CYP3A4 inhibitor, markedly reduced the oxidation of terfenadine (26% of controls) in human liver microsomes, but showed only a marginal inhibition on the oxidation of astemizole (81% of controls). Three metabolites of astemizole were detected in a liver microsomal system, i.e. desmethylastemizole (DES-AST), 6-hydroxyastemizole (6OH-AST) and norastemizole (NOR-AST) at the ratio of 7.4 : 2.8 : 1. Experiments with recombinant P450s and antibodies indicate a negligible role for CYP3A4 on the main metabolic route of astemizole, i.e. formation of DES-AST, although CYP3A4 may mediate the relatively minor metabolic routes to 6OH-AST and NOR-AST. Recombinant CYP2D6 catalysed the formation of 6OH-AST and DES-AST. Studies with human liver microsomes, however, suggest a major role for a mono P450 in DES-AST formation.

Conclusions: In contrast to terfenadine, a minor role for CYP3A4 and involvement of multiple P450 isozymes are suggested in the metabolism of astemizole. These differences in P450 isozymes involved in the metabolism of astemizole and terfenadine may associate with distinct pharmacokinetic influences observed with coadministration of drugs metabolized by CYP3A4.

Publication types

  • Comparative Study

MeSH terms

  • Anti-Allergic Agents / metabolism*
  • Anti-Bacterial Agents / pharmacology
  • Antibodies / pharmacology
  • Astemizole / metabolism*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / immunology
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Interactions
  • Humans
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism*
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Mixed Function Oxygenases / immunology
  • Mixed Function Oxygenases / metabolism*
  • Recombinant Proteins / metabolism
  • Statistics as Topic
  • Substrate Specificity
  • Terfenadine / metabolism*
  • Troleandomycin / pharmacology


  • Anti-Allergic Agents
  • Anti-Bacterial Agents
  • Antibodies
  • Cytochrome P-450 Enzyme Inhibitors
  • Recombinant Proteins
  • Terfenadine
  • Astemizole
  • Cytochrome P-450 Enzyme System
  • Troleandomycin
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human