title: Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol.
abstract: OBJECTIVE
  We evaluated the inhibitory effect of haloperidol and its metabolites on CYP2D6 activity in order to better understand the potential role of these metabolites in drug interactions involving haloperidol.
  
  
  METHODS
  The inhibitory effects of haloperidol and five of its metabolites on dextrorphan formation from dextromethorphan, a marker probe of CYP2D6 activity, were measured in human liver microsomal preparations. Apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data.
  
  
  RESULTS
  Racemic reduced haloperidol and its metabolite, RHPTP competitively inhibited dextromethorphan O-demethylation with estimated Ki values (0.24 microM and 0.09 microM, respectively) that were substantially lower than that of haloperidol (0.89 microM). The inhibitory effect of S(-)-reduced haloperidol was more potent than the R(+)-enantiomer, with estimated Ki values of 0.11 microM and 1.1 microM, respectively. The pyridinium metabolite of haloperidol, HPP+ inhibited the enzyme activity noncompetitively with a Ki value of 0.79 microM. The N-dealkylated metabolites of haloperidol (FBPA and CPHP) had a diminished inhibitory potency. While FBPA showed no notable inhibitory effect on dextrorphan formation, CPHP showed moderate competitive inhibition with a Ki value of 20.9 microM.
  
  
  CONCLUSIONS
  The principal metabolites of haloperidol inhibit CYP2D6, suggesting that they might contribute to the inhibitory effects of the drug. Reduced haloperidol seems to inhibit CYP2D6 activity in an enantioselective manner with the physiologically occurring S(-) enantiomer being more potent.
authors.affiliation: Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Georgetown University Medical Center, Washington, DC 20007, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Shin
authors.forename: K
authors.initials: K
authors.lastname: Kane
authors.forename: D A
authors.initials: DA
authors.lastname: Flockhart
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D015415:Biomarkers; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003917:Dextrorphan / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D006220:Haloperidol / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010636:Phenols / Q000494:pharmacology; D020005:Propanols / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D015415:Biomarkers; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010636:Phenols; D020005:Propanols; D003917:Dextrorphan; C417567:3-(4-hydroxyphenyl)propanol; C040692:4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanol; D006220:Haloperidol