title: Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol.
abstract: OBJECTIVE
  Therapeutic drug monitoring (TDM) of antipsychotics can aid in therapy optimization, explaining adverse effects or non-response. One reason for therapeutic failure or adverse effects is caused by genetic variations in the cytochrome P450 drug-metabolizing genes. The aim of this study was to evaluate the impact of CYP2D6 polymorphisms on steady-state serum concentrations of antipsychotics metabolized by CYP2D6, taking into account the co-medication with CYP2D6 inhibitors.
  
  
  METHODS
  Serum and EDTA samples were collected from 82 psychiatric patients. After a liquid-liquid extraction, serum samples were analyzed using an ultra-high performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method for quantification of the antipsychotics. CYP2D6 genotyping was performed using the Luminex xTAG® CYP2D6 Kit v3 (Luminex Corporation). Patients were divided into five phenotype subgroups by calculation of the activity score (AS): poor metabolizers (PM; AS 0), intermediate metabolizers (IM; AS 0.5-1), extensive metabolizers with slow activity (EM-s; AS 1-1.5), extensive metabolizers with fast activity (EM-f; AS 2), and ultra-rapid metabolizers (UM; AS >2). The influence of the phenotypes on the concentration-to-dose and metabolite-to-parent ratios was evaluated.
  
  
  RESULTS
  Overall, 6.1 % UM (n = 5), 25.6 % EM-f (n = 21), 46.3 % EM-s (n = 38), 1.2 % EM-s/EM-f (n = 1), 6.1 % IM (n = 5), and 14.6 % PM (n = 12) were found, taking co-administration of strong and moderate CYP2D6 inhibitors into account (phenoconversion). It was demonstrated that CYP2D6 polymorphisms affect the serum concentrations of aripiprazole (n = 18), haloperidol (n = 11), risperidone (n = 20), and zuclopenthixol (n = 6), while no influence was seen on the paliperidone serum concentrations (n = 31).
  
  
  CONCLUSIONS
  Even with a small number of patients per antipsychotic, the importance of CYP2D6 genotyping was still clearly stated. This study illustrates the high potential of combining TDM and CYP2D6 genotyping in clinical practice.
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium. lisbeth.patteet@uantwerp.be.
authors.forename: Patteet
authors.initials: P
authors.lastname: Lisbeth
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology, Institute de recherche expérimentale et clinique, Université catholique de Louvain, Avenue E. Mounier 53, B-1200, Brussels, Belgium.|Department of Clinical Chemistry, Clinique Universitaires Saint-Luc, Université catholique de Louvain, Avenue Hippocrate 10, B-1200, Brussels, Belgium.
authors.forename: Haufroid
authors.initials: H
authors.lastname: Vincent
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
authors.forename: Maudens
authors.initials: M
authors.lastname: Kristof
authors.affiliation: Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.|Psychiatric Centre Sint-Norbertushuis, Stationstraat 22C, B-2570, Duffel, Belgium.
authors.forename: Sabbe
authors.initials: S
authors.lastname: Bernard
authors.affiliation: Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.|Psychiatric Hospital Broeders Alexianen, Provinciesteenweg 408, B-2530, Boechout, Belgium.
authors.forename: Morrens
authors.initials: M
authors.lastname: Manuel
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.|Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060, Antwerp, Belgium.
authors.forename: Neels
authors.initials: N
authors.lastname: Hugo
mesh_terms: D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics; D000068180:Aripiprazole / Q000097:blood / Q000493:pharmacokinetics; D003006:Clopenthixol / Q000097:blood / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006220:Haloperidol / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D000068882:Paliperidone Palmitate / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D000068180:Aripiprazole; D003006:Clopenthixol; D019389:Cytochrome P-450 CYP2D6; D006220:Haloperidol; D000068882:Paliperidone Palmitate
keywords: Antipsychotics; CYP2D6; Genotyping; Therapeutic drug monitoring