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Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol.
Lisbeth, Patteet; Vincent, Haufroid; Kristof, Maudens; Bernard, Sabbe; Manuel, Morrens; Hugo, Neels.
Afiliação
  • Lisbeth P; Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium. lisbeth.patteet@uantwerp.be.
  • Vincent H; 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.
  • Kristof M; Department of Clinical Chemistry, Clinique Universitaires Saint-Luc, Université catholique de Louvain, Avenue Hippocrate 10, B-1200, Brussels, Belgium.
  • Bernard S; Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
  • Manuel M; Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
  • Hugo N; Psychiatric Centre Sint-Norbertushuis, Stationstraat 22C, B-2570, Duffel, Belgium.
Eur J Clin Pharmacol ; 72(2): 175-84, 2016 Feb.
Article em En | MEDLINE | ID: mdl-26514968
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antipsicóticos / Clopentixol / Citocromo P-450 CYP2D6 / Palmitato de Paliperidona / Aripiprazol / Haloperidol Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Eur J Clin Pharmacol Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antipsicóticos / Clopentixol / Citocromo P-450 CYP2D6 / Palmitato de Paliperidona / Aripiprazol / Haloperidol Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Eur J Clin Pharmacol Ano de publicação: 2016 Tipo de documento: Article