Research article summary (published 30 Jul 2009):

ABCB1 and cytochrome P450 polymorphisms: clinical pharmacogenetics of clozapine.

Full Abstract

To examine the genetic factors influencing clozapine kinetics in vivo, 75 patients treated with clozapine were genotyped for CYPs and ABCB1 polymorphisms and phenotyped for CYP1A2 and CYP3A activity. CYP1A2 activity and dose-corrected trough steady-state plasma concentrations of clozapine correlated significantly (r = -0.61; P = 1 x 10), with no influence of the CYP1A2*1F genotype (P = 0.38). CYP2C19 poor metabolizers (*2/*2 genotype) had 2.3-fold higher (P = 0.036) clozapine concentrations than the extensive metabolizers (non-*2/*2). In patients comedicated with fluvoxamine, a strong CYP1A2 inhibitor, clozapine and norclozapine concentrations correlate with CYP3A activity (r = 0.44, P = 0.075; r = 0.63, P = 0.007, respectively). Carriers of the ABCB1 3435TT genotype had a 1.6-fold higher clozapine plasma concentrations than noncarriers (P = 0.046). In conclusion, this study has shown for the first time a significant in vivo role of CYP2C19 and the P-gp transporter in the pharmacokinetics of clozapine. CYP1A2 is the main CYP isoform involved in clozapine metabolism, with CYP2C19 contributing moderately, and CYP3A4 contributing only in patients with reduced CYP1A2 activity. In addition, ABCB1, but not CYP2B6, CYP2C9, CYP2D6, CYP3A5, nor CYP3A7 polymorphisms, influence clozapine pharmacokinetics.

Author information

Author/s: Jaquenoud Sirot, Eveline (E); Knezevic, Branka (B); Morena, Gina Perla (GP); Harenberg, Sabine (S); Oneda, Beatrice (B); Crettol, Séverine (S); Ansermot, Nicolas (N); Baumann, Pierre (P); Eap, Chin B (CB);

Affiliation: Psychiatrische Dienste Aargau AG, mediQ, Klinik Königsfelden, Brugg.

Journal and publication information

Publication Type: Clinical Trial; Journal Article; Multicenter Study

Journal: Journal of clinical psychopharmacology (J Clin Psychopharmacol), published in United States. (Language: eng)

Reference: 2009-Aug; vol 29 (issue 4) : pp 319-26

Dates: Created 2009/07/13; Completed 2009/09/17;

PMID: 19593168, status: MEDLINE (last retrieval date: 9/17/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adult Aged Aged, 80 and over Antipsychotic Agents - administration & dosage; blood; pharmacokinetics Aryl Hydrocarbon Hydroxylases - genetics Caffeine - metabolism Clozapine - administration & dosage; analogs & derivatives; blood; pharmacokinetics Cytochrome P-450 CYP1A2 - genetics Cytochrome P-450 Enzyme System - antagonists & inhibitors; genetics; metabolism Enzyme Inhibitors - administration & dosage Female Fluvoxamine - administration & dosage

Fluvoxamine - administration & dosage Genotype Humans Male Midazolam - metabolism Middle Aged P-Glycoprotein - genetics; metabolism Phenotype Polymorphism, Genetic Substrate Specificity Switzerland Young Adult

Associated Chemicals: ABCB1 protein, human (0) ; Antipsychotic Agents (0) ; Enzyme Inhibitors (0) ; P-Glycoprotein (0) ; Fluvoxamine (54739-18-3) ; Clozapine (5786-21-0) ; Caffeine (58-08-2) ; Midazolam (59467-70-8) ; norclozapine (6104-71-8) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Aryl Hydrocarbon Hydroxylases (EC 1.14.14.1) ; CYP1A2 protein, human (EC 1.14.14.1) ; CYP2C19 protein, human (EC 1.14.14.1) ; CYP3A protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP1A2 (EC 1.14.14.1)

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