title: Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine.
abstract: Clozapine use is associated with leukopenia and more rarely agranulocytosis, which may be lethal. The drug and its metabolites are proposed to interact with the multidrug resistance transporter (ABCB1/MDR1) gene product, P-glycoprotein (P-gp). Among various P-glycoprotein genetic polymorphisms, nucleotide changes in exons 26 (C3435T), 21 (G2677T), and 12 (C1236T) have been implicated for changes in pharmacokinetics and pharmacodynamics of many substrate drugs. In this study, we aimed to investigate the association between these specific ABCB1 polymorphisms and clozapine-associated agranulocytosis (CAA). Ten patients with a history of CAA and 91 control patients without a history of CAA, despite 10 years of continuous clozapine use, were included. Patient recruitment and blood sample collection were conducted at the Hacettepe University Faculty of Medicine, Department of Psychiatry, in collaboration with the members of the Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, working in various psychiatry clinics. After DNA extraction from peripheral blood lymphocytes, genotyping was performed using polymerase chain reaction and endonuclease digestion. Patients with CAA had shorter duration of clozapine use but did not show any significant difference in other clinical, sociodemographic characteristics and in genotypic or allelic distributions of ABCB1 variants and haplotypes compared with control patients. Among the 10 patients with CAA, none carried the ABCB1 all-variant haplotype (TT-TT-TT), whereas the frequency of this haplotype was approximately 12% among the controls. Larger sample size studies and thorough genetic analyses may reveal both genetic risk and protective factors for this serious adverse event.
authors.affiliation: From the Departments of *Psychiatry and †Pharmacology, Hacettepe University Faculty of Medicine, Ankara, Turkey; ‡Department of Pharmacology, Faculty of Medicine, BAU International University, Batumi, GA; and §Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, Ankara, Turkey.
authors.forename: A Elif
authors.initials: AE
authors.lastname: Anıl Yağcioğlu
authors.forename: Gökhan
authors.initials: G
authors.lastname: Yoca
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Ayhan
authors.forename: R Özgür
authors.initials: RÖ
authors.lastname: Karaca
authors.forename: Lokman
authors.initials: L
authors.lastname: Çevik
authors.forename: Ahmet
authors.initials: A
authors.lastname: Müderrisoğlu
authors.forename: Mustafa T
authors.initials: MT
authors.lastname: Göktaş
authors.forename: Nurhayat
authors.initials: N
authors.lastname: Eni
authors.forename: M Kâzım
authors.initials: MK
authors.lastname: Yazıcı
authors.forename: Atilla
authors.initials: A
authors.lastname: Bozkurt
authors.forename: Melih O
authors.initials: MO
authors.lastname: Babaoğlu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics*; D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects*; D003024:Clozapine / Q000009:adverse effects*; D006801:Humans; D008875:Middle Aged; D000071184:Pharmacogenomic Variants / Q000187:drug effects / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D014421:Turkey; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D014150:Antipsychotic Agents; D003024:Clozapine