title: Cytochrome P450 and ABCB1 genetics: association with quetiapine and norquetiapine plasma and cerebrospinal fluid concentrations and with clinical response in patients suffering from schizophrenia. A pilot study.
abstract: Variability in response to atypical antipsychotic drugs is due to genetic and environmental factors. Cytochrome P450 (CYP) isoforms are implicated in the metabolism of drugs, while the P-glycoprotein transporter (P-gp), encoded by the ABCB1 gene, may influence both the blood and brain drug concentrations. This study aimed to identify the possible associations of CYP and ABCB1 genetic polymorphisms with quetiapine and norquetiapine plasma and cerebrospinal fluid (CSF) concentrations and with response to treatment. Twenty-two patients with schizophrenia receiving 600 mg of quetiapine daily were genotyped for four CYP isoforms and ABCB1 polymorphisms. Quetiapine and norquetiapine peak plasma and CSF concentrations were measured after 4 weeks of treatment. Stepwise multiple regression analysis revealed that ABCB1 3435C > T (rs1045642), 2677G > T (rs2032582) and 1236C > T (rs1128503) polymorphisms predicted plasma quetiapine concentrations, explaining 41% of the variability (p = 0.001). Furthermore, the ABCB1 polymorphisms predicted 48% (p = 0.024) of the variability of the Δ PANSS total score, with the non-carriers of the 3435TT showing higher changes in the score. These results suggest that ABCB1 genetic polymorphisms may be a predictive marker of quetiapine treatment in schizophrenia.
authors.affiliation: Department of Psychiatry and Psychotherapy, Klinikum Fulda gAG, Fulda, Germany. georg.nikisch@klinikum-fulda.de
authors.forename: Georg
authors.initials: G
authors.lastname: Nikisch
authors.forename: Pierre
authors.initials: P
authors.lastname: Baumann
authors.forename: Beatrice
authors.initials: B
authors.lastname: Oneda
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kiessling
authors.forename: Heike
authors.initials: H
authors.lastname: Weisser
authors.forename: Aleksander A
authors.initials: AA
authors.lastname: Mathé
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshitake
authors.forename: Jan
authors.initials: J
authors.lastname: Kehr
authors.forename: Georg
authors.initials: G
authors.lastname: Wiedemann
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003987:Dibenzothiazepines / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010597:Pharmacogenetics; D010865:Pilot Projects; D011569:Psychiatric Status Rating Scales; D000069348:Quetiapine Fumarate; D018570:Risk Assessment; D012307:Risk Factors; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D012565:Schizophrenic Psychology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D003577:Cytochrome P-450 Enzyme System