Effect of caffeine on clozapine pharmacokinetics in healthy volunteers

Br J Clin Pharmacol. 2000 Jan;49(1):59-63. doi: 10.1046/j.1365-2125.2000.00111.x.


Aims: To assess the effects of caffeine on the pharmacokinetics of clozapine in healthy volunteers.

Methods: This was an open label randomized crossover study in 12 nonsmoking healthy male volunteers. The subjects received a single oral dose of 12.5 mg clozapine in each phase with or without concomitant intake of caffeine (mean dose: 550 mg day-1, range: 400-1000 mg day-1 ). Serum concentrations of clozapine and its metabolites desmethyl-clozapine and clozapine-N-oxide were measured during a 48 h period in each phase. In addition, serum concentrations of caffeine and the metabolite paraxanthine were monitored.

Results: A 19% increase in mean clozapine AUC(0,infinity) (P=0.05) and a 14% decrease of mean oral clearance of clozapine were observed during concomitant intake of caffeine (P=0.05) compared with intake of only clozapine. Statistically significant decreases of mean ratios between AUC(0, 12h) for desmethyl-clozapine and AUC(0,12h) for clozapine (-18%), and between AUC(0,12h) for clozapine-N-oxide and AUC(0,12h) for clozapine (-23%) were observed during the caffeine phase (P=0.03 and 0.02, respectively). Oral clearance of clozapine and the ratio AUC(0, 12h) for desmethyl-clozapine/AUC(0,12h) for clozapine were correlated with the paraxanthine/caffeine ratio in serum after intake of caffeine (rs=0.62; P=0.03 and rs=0.77; P=0.003, respectively).

Conclusions: These results suggest that caffeine in daily doses of 400-1000 mg inhibits the metabolism of clozapine to an extent that might be clinically significant in certain individuals.

Publication types

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

MeSH terms

  • Adult
  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / blood
  • Antipsychotic Agents / pharmacokinetics*
  • Area Under Curve
  • Biotransformation
  • Caffeine / blood
  • Caffeine / pharmacology*
  • Central Nervous System Stimulants / blood
  • Central Nervous System Stimulants / pharmacology*
  • Chromatography, High Pressure Liquid
  • Clozapine / adverse effects
  • Clozapine / blood
  • Clozapine / pharmacokinetics*
  • Cross-Over Studies
  • Humans
  • Male
  • Theophylline / blood


  • Antipsychotic Agents
  • Central Nervous System Stimulants
  • Caffeine
  • Theophylline
  • Clozapine
  • 1,7-dimethylxanthine