Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2-receptor antagonists

Clin Pharmacol Ther. 1999 Apr;65(4):369-76. doi: 10.1016/S0009-9236(99)70129-3.


The isozymes CYP1A2, CYP2D6, and CYP3A4/5 are involved in the majority of all cytochrome P450-mediated drug biotransformations. In this study we investigated the inhibition profiles of CYP1A2 (substrate: caffeine) CYP2D6 (substrate: dextromethorphan), and CYP3A4/5 (substrate: dextrorphan) by cimetidine, ranitidine, and the novel H2-receptor antagonist ebrotidine in human liver microsomes. The inhibitory effect of the drugs on the enzymes activities were as follows: CYP1A2: cimetidine >> ranitidine = ebrotidine; CYP2D6: cimetidine >>> ranitidine = ebrotidine; CYP3A4/5: ebrotidine > cimetidine >>> ranitidine. The inhibition of CYP3A4/5 enzyme activity by ebrotidine was competitive. To test whether the inhibitory effect of ebrotidine in CYP3A activity was also found in vivo, we analyzed the biodisposition of midazolam in 8 healthy volunteers. Midazolam biodisposition was significantly reduced when administered together with cimetidine (P < .05), whereas no significant inhibition was observed with ebrotidine or ranitidine compared with placebo. Psychomotor performance analysis revealed no significant effect of the observed reduction on midazolam biodisposition. We concluded that patients who are receiving treatment with drugs metabolized through CYP3A may experience enhanced drug effects as a result of pharmacokinetic interaction when treated concomitantly with cimetidine. In contrast, the effect of ranitidine or ebrotidine on CYP3A activity in vivo seems to have little clinical significance.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Anxiety Agents / pharmacokinetics*
  • Antitussive Agents / pharmacokinetics
  • Aryl Hydrocarbon Hydroxylases*
  • Benzenesulfonates / pharmacology
  • Caffeine / pharmacokinetics
  • Central Nervous System Stimulants / pharmacokinetics
  • Cimetidine / pharmacology
  • Cytochrome P-450 CYP1A2 Inhibitors*
  • Cytochrome P-450 CYP2D6 Inhibitors*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Dextromethorphan / pharmacokinetics
  • Double-Blind Method
  • Histamine H2 Antagonists / pharmacology*
  • Humans
  • In Vitro Techniques
  • Male
  • Methylation / drug effects
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology*
  • Midazolam / pharmacokinetics*
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors*
  • Psychomotor Performance / drug effects
  • Ranitidine / pharmacology
  • Thiazoles / pharmacology


  • Anti-Anxiety Agents
  • Antitussive Agents
  • Benzenesulfonates
  • Central Nervous System Stimulants
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Histamine H2 Antagonists
  • Thiazoles
  • Caffeine
  • Dextromethorphan
  • Cimetidine
  • Ranitidine
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Midazolam
  • ebrotidine