Metabolism of the active metabolite of quetiapine, N-desalkylquetiapine in vitro

Drug Metab Dispos. 2012 Sep;40(9):1778-84. doi: 10.1124/dmd.112.045237. Epub 2012 Jun 11.

Abstract

The antipsychotic drug quetiapine has been approved for the treatment of unipolar and bipolar depression. The antidepressant activity is considered to be mediated by the active metabolite N-desalkylquetiapine, which is mainly formed by CYP3A4. Little is known about the subsequent elimination of this metabolite. Therefore, this study investigated the possible involvement of cytochrome P450 (P450) enzymes in the metabolism of N-desalkylquetiapine. Screening for and interpretation of metabolites were performed by incubating N-desalkylquetiapine in human liver microsomes (HLM) followed by liquid chromatography-tandem mass spectrometry. The possible involvement of P450 enzymes in N-desalkylquetiapine metabolism was evaluated by coincubation of selective P450 inhibitors in HLM and subsequent experiments with recombinant human P450 enzymes. In HLM experiments, three chromatographic peaks were interpreted as possible metabolites of N-desalkylquetiapine, namely, N-desalkylquetiapine sulfoxide, 7-hydroxy-N-desalkylquetiapine, and an unrecognized metabolite (denoted M3). Inhibition of CYP2D6 (by quinidine) reduced formation of 7-hydroxy-N-desalkylquetiapine by 81%, whereas the CYP3A4 inhibitor ketoconazole inhibited formation of N-desalkylquetiapine sulfoxide and M3 by 65 and 34%, respectively. Inhibitors of CYP1A2, CYP2C9, and CYP2C19 showed only limited changes in metabolite formation. In recombinant systems, 7-hydroxy-N-desalkylquetiapine was exclusively formed by CYP2D6, whereas N-desalkylquetiapine sulfoxide and M3 were formed by both CYP3A4 and CYP2D6. Overall, intrinsic clearance of N-desalkylquetiapine was 12-fold higher by recombinant CYP2D6 relative to CYP3A4. In conclusion, N-desalkylquetiapine is metabolized by both CYP2D6 and CYP3A4 in vitro with preference for the former enzyme. The pharmacologically active metabolite, 7-hydroxy-N-desalkylquetiapine, was exclusively formed by CYP2D6, whereas the two other metabolites were mainly formed by CYP3A4.

MeSH terms

  • Antidepressive Agents / chemistry
  • Antidepressive Agents / metabolism*
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / metabolism*
  • Biotransformation
  • Chromatography, Liquid
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dealkylation
  • Dibenzothiazepines / chemistry
  • Dibenzothiazepines / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydroxylation
  • Kinetics
  • Liver / drug effects
  • Liver / enzymology*
  • Microsomes, Liver / enzymology
  • Models, Biological
  • Molecular Structure
  • Quetiapine Fumarate
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Substrate Specificity
  • Sulfoxides / metabolism
  • Tandem Mass Spectrometry

Substances

  • Antidepressive Agents
  • Antipsychotic Agents
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 CYP3A Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Dibenzothiazepines
  • Enzyme Inhibitors
  • Recombinant Proteins
  • Sulfoxides
  • Quetiapine Fumarate
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human