Pharmacogenetics of clozapine: in vivo role of cytochrome P450 isoforms and P-Glycoprotein

Détails

ID Serval
serval:BIB_7BD695DD2CB3
Type
Actes de conférence (partie): contribution originale à la littérature scientifique, publiée à l'occasion de conférences scientifiques, dans un ouvrage de compte-rendu (proceedings), ou dans l'édition spéciale d'un journal reconnu (conference proceedings).
Sous-type
Abstract (résumé de présentation): article court qui reprend les éléments essentiels présentés à l'occasion d'une conférence scientifique dans un poster ou lors d'une intervention orale.
Collection
Publications
Institution
Titre
Pharmacogenetics of clozapine: in vivo role of cytochrome P450 isoforms and P-Glycoprotein
Titre de la conférence
Pharmacopsychiatry
Auteur(s)
Jaquenoud Sirot Eveline, Knezevic B., Perla Morena Gina, Baumann Pierre, Eap Chin Bin
ISBN
0176-3679
Statut éditorial
Publié
Date de publication
2008
Peer-reviewed
Oui
Volume
41
Série
Pharmacopsychiatry
Langue
anglais
Notes
SAPHIRID:69091
Résumé
The in vivo implication of various cytochrome P450 isoforms and of P-glycoprotein on clozapine kinetics is still unclear. We aimed to thoroughly examine the genetic factors influencing clozapine kinetics.
75 patients treated with clozapine were genotyped for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4,5,7 and ABCB1. In addition, patients were phenotyped with caffeine and midazolam to assess CYP1A2 and CYP3A4/5 activity, respectively. The steady-state trough plasma concentrations of clozapine and norclozapine were measured.
A strong correlation was measured between CYP1A2 activity (measured by the caffeine/paraxanthine ratio) and plasma concentrations of clozapine (r=-.606; p<0.001), and norclozapine (r=-.480; p<0.001) but CYP1A2*1F genotypes did not influence neither clozapine nor norclozapine plasma concentrations (n.s., p=0.5). No correlation was found between clozapine (r=-0.16, p=0.16) plasma levels and CYP3A activity as expressed by the 1-OH midazolam to midazolam ratios. CYP2C19 genotypes significantly influence clozapine plasma concentrations, with the CYP2C19 poor metabolizers (*2/*2 genotypes) having 2.3 (p=0.036) and 1.2 (n.s.) fold, respectively, higher clozapine and norclozapine plasma concentrations than the extensive metabolizers (*1/*1, *1/*2). Smokers had lower clozapine and norclozapine concentrations than non-smokers. Patients treated with fluvoxamine (25-300mg/day), an antidepressant and a strong CYP1A2 inhibitor, had a median 3.5 and 2.4 fold increased clozapine and norclozapine concentrations, respectively as compared to patients with clozapine only. The CYP2B6, CYP2C9, CYP2D6, CYP3A4 CYP3A5, CYP3A7 and ABCB1 genotypes did not influence clozapine plasma concentrations.
In vivo, CYP1A2 is the main CYP isoform involved in clozapine metabolism, with CYP2C19 contributing moderately, while CYP3A might only be significant at high clozapine plasma concentrations.
Création de la notice
18/09/2008 16:54
Dernière modification de la notice
20/08/2019 15:37
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