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Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

An Erratum to this article was published on 13 October 2016

Abstract

Purpose

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.

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Abbreviations

AS:

Activity score

ARI:

Aripiprazole

C/D:

Concentration-to-dose ratio

CYP:

Cytochrome P450

DD:

Daily dose

DARI:

Dehydro-aripiprazole

DEF:

Allele with deficient function

EM:

Extensive metabolizer

EM-f:

Extensive metabolizer with fast activity

EM-s:

Extensive metabolizer with slow activity

HAL:

Haloperidol

IM:

Intermediate metabolizer

JT:

Jonckheere-Terpstra test

MW-U:

Mann-Whitney U test

M/P:

Metabolite-to-parent ratio

NF:

Allele with normal function

PAL:

Paliperidone

PM:

Poor metabolizer

RED:

Allele with reduced function

RHAL:

Reduced haloperidol

RIS:

Risperidone

TDM:

Therapeutic drug monitoring

UHPLC-MS/MS:

Ultra-high performance liquid chromatography-tandem mass spectrometry

UM:

Ultra-rapid metabolizer

ZUC:

Zuclopenthixol

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Authors and Affiliations

  1. Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium

    Patteet Lisbeth, Maudens Kristof & Neels Hugo

  2. 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

    Haufroid Vincent

  3. Department of Clinical Chemistry, Clinique Universitaires Saint-Luc, Université catholique de Louvain, Avenue Hippocrate 10, B-1200, Brussels, Belgium

    Haufroid Vincent

  4. Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium

    Sabbe Bernard & Morrens Manuel

  5. Psychiatric Centre Sint-Norbertushuis, Stationstraat 22C, B-2570, Duffel, Belgium

    Sabbe Bernard

  6. Psychiatric Hospital Broeders Alexianen, Provinciesteenweg 408, B-2530, Boechout, Belgium

    Morrens Manuel

  7. Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060, Antwerp, Belgium

    Neels Hugo

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  1. Patteet Lisbeth
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Correspondence to Patteet Lisbeth.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00228-016-2144-8.

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Lisbeth, P., Vincent, H., Kristof, M. et al. Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol. Eur J Clin Pharmacol 72, 175–184 (2016). https://doi.org/10.1007/s00228-015-1965-1

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