Effects of erythromycin and roxithromycin on oxidation of testosterone and nifedipine catalyzed by CYP3A4 in human liver microsomes

J Toxicol Sci. 1996 Nov;21(4):215-26. doi: 10.2131/jts.21.4_215.


Roxithromycin and erythromycin were incubated with rat and human liver microsomal or reconstituted cytochrome P450 (P450 or CYP) monooxygenase systems in the presence of an NADPH-generating system, and the effects of these chemicals on testosterone 6 beta-hydroxylation and nifedipine oxidation activities were compared with those of typical CYP3A4 inhibitors including ketoconazole, troleandomycin, and gestodene. Roxithromycin and erythromycin were found to be relatively weak inhibitors of testosterone 6 beta-hydroxylation and nifedipine oxidation activities by rat and human liver microsomes or by reconstituted systems containing CYP3A4/5. Formation of an inhibitory P450-metabolite complex was determined spectrally by incubating troleandomycin with human liver microsomes; the extents of the complex formation were lesser in liver microsomes of humans than those of rats treated with dexamethasone. Erythromycin and roxithromycin were also activated slightly by rat liver microsomes to form P450.Fe(II)-metabolite complex, although these chemicals caused very little or undetectable levels, respectively, of spectral changes by human liver microsomes even when a human sample which contained relatively high levels of CYP3A4 was used. These results suggested that roxithromycin and erythromycin were relatively less potent to inhibit CYP3A4-catalytic activities in human liver microsomes, because of their low capabilities to form P450.Fe(II)-metabolite complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Catalysis
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Erythromycin / pharmacology*
  • Humans
  • Ketoconazole / pharmacology
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Mixed Function Oxygenases / pharmacology*
  • Nifedipine / metabolism*
  • Oxidation-Reduction
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / pharmacology
  • Roxithromycin / pharmacology*
  • Testosterone / metabolism*
  • Troleandomycin / pharmacology


  • Anti-Bacterial Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Recombinant Proteins
  • Roxithromycin
  • Testosterone
  • Erythromycin
  • Cytochrome P-450 Enzyme System
  • Troleandomycin
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Nifedipine
  • Ketoconazole