ABCB1 and Cytochrome P450 Polymorphisms
| Autor: | Séverine Crettol, Pierre Baumann, Beatrice Oneda, Eveline Jaquenoud Sirot, Sabine Harenberg, Gina Perla Morena, Branka Knezevic, Nicolas Ansermot, Chin B. Eap |
|---|---|
| Přispěvatelé: | University of Zurich |
| Rok vydání: | 2009 |
| Předmět: |
Male
CYP2B6 10039 Institute of Medical Genetics Pharmacology Substrate Specificity 2738 Psychiatry and Mental Health Cytochrome P-450 Enzyme System Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors 2736 Pharmacology (medical) Pharmacology (medical) Enzyme Inhibitors Clozapine Aged 80 and over Middle Aged Psychiatry and Mental health Phenotype Female Aryl Hydrocarbon Hydroxylases Switzerland Antipsychotic Agents medicine.drug Adult CYP2D6 medicine.medical_specialty ATP Binding Cassette Transporter Subfamily B Genotype medicine.drug_class Midazolam Atypical antipsychotic 610 Medicine & health CYP2C19 Biology Young Adult Cytochrome P-450 CYP1A2 Caffeine Internal medicine medicine Humans ATP Binding Cassette Transporter Subfamily B Member 1 CYP2C9 Aged Polymorphism Genetic CYP3A4 Cytochrome P-450 CYP2C19 Endocrinology Fluvoxamine 570 Life sciences biology Pharmacogenetics |
| Zdroj: | Journal of Clinical Psychopharmacology. 29:319-326 |
| ISSN: | 0271-0749 |
| DOI: | 10.1097/jcp.0b013e3181acc372 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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