Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations

J Clin Pharmacol. 2001 Aug;41(8):823-32. doi: 10.1177/00912700122010717.


The authors assessed the in vitro contribution of cytochrome P450 (CYP) isoforms 1A2, 3A4, 2C9, 2C19, and 2D6 to the N-demethylation of clozapine mediated by human liver microsomal preparations (HLM). In contrast to previous studies, the authors focused on a relatively low hepatic concentration level, 5 microM, to assess the conditions at a therapeutically relevant hepatic concentration level of clozapine. The optimal concentrations of specific inhibitors were initially established using cDNA-expressed CYP isoforms. The mean contributions of CYPs 1A2, 2C19, 3A4, 2C9, and 2D6 amounted to 30%, 24%, 22%, 12%, and 6%, respectively, with regard to the total HLM-mediated N-demethylation. Thus, the present in vitro study on clozapine N-demethylation suggests that CYP1A2 is the most important form at low concentrations, which is in agreement with clinical findings. CYP2C19 is also of considerable importance, while the roles of CYP2C9 and 2D6 are more modest. CYP3A4 attained a dominating role with an average contribution of 37% at a high clozapine concentration (50 microM). The rate of other metabolic routes mediated by CYP2D6 only corresponded to about one fifth of the CYP2D6 catalyzed N-demethylation rate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents / metabolism*
  • Aryl Hydrocarbon Hydroxylases*
  • Clozapine* / metabolism*
  • Cytochrome P-450 CYP1A2 / physiology
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP2D6 / physiology
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / physiology*
  • Dealkylation
  • Humans
  • Microsomes, Liver / metabolism
  • Mixed Function Oxygenases / physiology
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / physiology


  • Antipsychotic Agents
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Steroid Hydroxylases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP1A2 protein, human
  • CYP2C19 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • Steroid 16-alpha-Hydroxylase
  • CYP3A4 protein, human
  • Clozapine