title: Pharmacogenetics of quetiapine in healthy volunteers: association with pharmacokinetics, pharmacodynamics, and adverse effects.
abstract: Quetiapine is an atypical antipsychotic used for treatment of schizophrenia. Variability in response to this drug may be associated with pharmacogenetics. The aim of this study was to identify genetic markers related to the pharmacokinetics, pharmacodynamics, and adverse effects of quetiapine. The study population comprised 79 healthy volunteers from two bioequivalence trials who were genotyped to identify polymorphisms in genes encoding enzymes, receptors, and transporters. Quetiapine plasma levels were quantified using high-performance liquid chromatography/mass spectrometry. Prolactin plasma levels were detected by indirect chemiluminescence. Possible adverse effects were recorded throughout the study. Factors with P value of 0.1 or less in the univariate analysis were included in a multiple regression analysis (logistic regression for adverse reactions). The area under the curve and clearance of quetiapine were affected by polymorphisms in CYP1A2 and DRD3, respectively. Men had a lower quetiapine area under the curve compared with women. Prolactin iC(max) was higher in volunteers harboring polymorphisms in CYP2C19 and AGT. An association was detected between polymorphisms in CYP1A1 and CYP2C9 and somnolence. Several polymorphisms are responsible for differences in the pharmacokinetics, pharmacodynamics, and safety of quetiapine in healthy individuals.
authors.affiliation: aService of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando bLiver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IP) cCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III dPharmacology Department, School of Medicine, Service of Clinical Pharmacology, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Cabaleiro
authors.forename: Rosario
authors.initials: R
authors.lastname: López-Rodríguez
authors.forename: Manuel
authors.initials: M
authors.lastname: Román
authors.forename: Dolores
authors.initials: D
authors.lastname: Ochoa
authors.forename: Jesús
authors.initials: J
authors.lastname: Novalbos
authors.forename: Alberto
authors.initials: A
authors.lastname: Borobia
authors.forename: Antonio
authors.initials: A
authors.lastname: Carcas
authors.forename: Francisco
authors.initials: F
authors.lastname: Abad-Santos
mesh_terms: D000293:Adolescent; D000328:Adult; D000808:Angiotensinogen / Q000235:genetics*; D014150:Antipsychotic Agents; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003987:Dibenzothiazepines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D011388:Prolactin / Q000097:blood; D000069348:Quetiapine Fumarate; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D012727:Sex Characteristics; D055815:Young Adult
chemical_list: C534931:AGT protein, human; D014150:Antipsychotic Agents; C493593:DRD3 protein, human; D003987:Dibenzothiazepines; D050637:Receptors, Dopamine D3; D000808:Angiotensinogen; D000069348:Quetiapine Fumarate; D011388:Prolactin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C569463:CYP1A1 protein, human; C504573:CYP1A2 protein, human; C045793:CYP2C19 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19