In vitro study on the involvement of CYP1A2, CYP2D6 and CYP3A4 in the metabolism of haloperidol and reduced haloperidol

Eur J Clin Pharmacol. 1999 Oct;55(8):599-604. doi: 10.1007/s002280050679.


Objective: To investigate in vitro which CYP isoforms (CYP1A2, CYP2D6 and CYP3A4) are involved in the biotransformation of haloperidol (HAL) and reduced haloperidol (RHAL).

Methods: The biotransformation of HAL and RHAL is evaluated by measuring HAL and RHAL remaining after incubation with human liver microsomes and with supersomes from human baculovirus-infected cells expressing human P(450) isoforms. The influence of chemical- and immuno-inhibition of specific isoforms on the disappearance of HAL and RHAL was also studied.

Results: After 60-min incubation of 2 microM and 20 microM HAL or RHAL with human liver microsomes, for HAL, 58% and 64%, respectively, remained in the incubation mixture, for RHAL, 53% and 66%, respectively. Ketoconazole had the most pronounced inhibitory effect on the biotransformation of both substrates, while for quinidine and furafylline there was only a weak or no influence. Anti-CYP3A4 antibodies inhibited strongly the biotransformation of HAL and RHAL, while the influence of anti-CYP2D6 antibodies was much less pronounced. After incubation with supersomes of recombinant CYP3A4, HAL and RHAL disappeared rapidly; disappearance was slow after incubation with CYP2D6 supersomes, and negligible with CYP1A2 supersomes.

Conclusion: The results show that CYP3A4 is the most important CYP isoenzyme involved in the biotransformation of HAL and RHAL, and that the metabolism by CYP2D6 is only a minor pathway; CYP1A2 has no or only a negligible influence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biotransformation
  • Child
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism*
  • Dopamine Antagonists / metabolism*
  • Dopamine Antagonists / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Haloperidol / analogs & derivatives*
  • Haloperidol / metabolism*
  • Haloperidol / pharmacokinetics
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Microsomes, Liver / enzymology
  • Middle Aged
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Mixed Function Oxygenases / metabolism
  • Oxidation-Reduction
  • Theophylline / analogs & derivatives
  • Theophylline / pharmacology


  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Dopamine Antagonists
  • Enzyme Inhibitors
  • Isoenzymes
  • 4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanol
  • Cytochrome P-450 Enzyme System
  • Theophylline
  • furafylline
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Haloperidol