title: Genetic and Clinical Factors Affecting Plasma Clozapine Concentration.
abstract: OBJECTIVE
  To assess (1) the variance of plasma clozapine levels; (2) the relative importance of sex, smoking habits, weight, age, and specific genetic variants of cytochrome P450 1A2 (CYP1A2), uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4), and multidrug resistance protein 1 (MDR1) on plasma levels of clozapine; and (3) the relation between plasma clozapine levels, fasting glucose levels, and waist circumference.
  
  
  METHODS
  There were 113 patients on clozapine treatment recruited from psychosis outpatient clinics in Stockholm County, Sweden. Patients had genotype testing for single nucleotide polymorphisms: 2 in MDR1, 3 in CYP1A2, and 1 in UGT1A4. Multiple and logistic regression were used to analyze the relations.
  
  
  RESULTS
  There was a wide variation in plasma concentrations of clozapine (mean = 1,615 nmol/L, SD = 1,354 nmol/L), with 37% of the samples within therapeutic range (1,100-2,100 nmol/L). Smokers had significantly lower plasma clozapine concentrations than nonsmokers (P ≤ .03). There was a significant association between the rs762551 A allele of CYP1A2 and lower plasma clozapine concentration (P ≤ .05). Increased fasting glucose level was 3.7-fold more frequent in CC and CA genotypes than AA genotype (odds ratio = 0.27; 95% confidence interval, 0.10-0.72). There was no significant relation between higher fasting glucose levels, larger waist circumference, and higher clozapine levels.
  
  
  CONCLUSIONS
  It is difficult to predict plasma clozapine concentration, even when known individual and genetic factors are considered. Therefore, therapeutic drug monitoring is recommended in patients who are treated with clozapine.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, and Department of Adult Psychiatry, PRIMA Barn och Vuxenpsykiatri AB, Stockholm (Dr Olsson); Department of Psychiatry, Tiohundra AB, Norrtälje (Drs Edman and Ösby and Ms Hukic); Department of Neurobiology, Care Sciences and Society, Centre of Family Medicine, Karolinska Institutet, Stockholm (Drs Edman and Ösby); Center for Molecular Medicine, Karolinska University Hospital, Stockholm (Drs Edman, Lavebratt, and Ösby); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm (Dr Bertilsson); Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Drs Hukic and Lavebratt); and Department of Cardiology, Danderyd University Hospital, Karolinska Institutet, Stockholm (Dr Eriksson), Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Olsson
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, and Department of Adult Psychiatry, PRIMA Barn och Vuxenpsykiatri AB, Stockholm (Dr Olsson); Department of Psychiatry, Tiohundra AB, Norrtälje (Drs Edman and Ösby and Ms Hukic); Department of Neurobiology, Care Sciences and Society, Centre of Family Medicine, Karolinska Institutet, Stockholm (Drs Edman and Ösby); Center for Molecular Medicine, Karolinska University Hospital, Stockholm (Drs Edman, Lavebratt, and Ösby); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm (Dr Bertilsson); Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Drs Hukic and Lavebratt); and Department of Cardiology, Danderyd University Hospital, Karolinska Institutet, Stockholm (Dr Eriksson), Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Edman
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, and Department of Adult Psychiatry, PRIMA Barn och Vuxenpsykiatri AB, Stockholm (Dr Olsson); Department of Psychiatry, Tiohundra AB, Norrtälje (Drs Edman and Ösby and Ms Hukic); Department of Neurobiology, Care Sciences and Society, Centre of Family Medicine, Karolinska Institutet, Stockholm (Drs Edman and Ösby); Center for Molecular Medicine, Karolinska University Hospital, Stockholm (Drs Edman, Lavebratt, and Ösby); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm (Dr Bertilsson); Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Drs Hukic and Lavebratt); and Department of Cardiology, Danderyd University Hospital, Karolinska Institutet, Stockholm (Dr Eriksson), Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Bertilsson
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, and Department of Adult Psychiatry, PRIMA Barn och Vuxenpsykiatri AB, Stockholm (Dr Olsson); Department of Psychiatry, Tiohundra AB, Norrtälje (Drs Edman and Ösby and Ms Hukic); Department of Neurobiology, Care Sciences and Society, Centre of Family Medicine, Karolinska Institutet, Stockholm (Drs Edman and Ösby); Center for Molecular Medicine, Karolinska University Hospital, Stockholm (Drs Edman, Lavebratt, and Ösby); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm (Dr Bertilsson); Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Drs Hukic and Lavebratt); and Department of Cardiology, Danderyd University Hospital, Karolinska Institutet, Stockholm (Dr Eriksson), Sweden.
authors.forename: Dzana Sudic
authors.initials: DS
authors.lastname: Hukic
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, and Department of Adult Psychiatry, PRIMA Barn och Vuxenpsykiatri AB, Stockholm (Dr Olsson); Department of Psychiatry, Tiohundra AB, Norrtälje (Drs Edman and Ösby and Ms Hukic); Department of Neurobiology, Care Sciences and Society, Centre of Family Medicine, Karolinska Institutet, Stockholm (Drs Edman and Ösby); Center for Molecular Medicine, Karolinska University Hospital, Stockholm (Drs Edman, Lavebratt, and Ösby); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm (Dr Bertilsson); Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Drs Hukic and Lavebratt); and Department of Cardiology, Danderyd University Hospital, Karolinska Institutet, Stockholm (Dr Eriksson), Sweden.
authors.forename: Catharina
authors.initials: C
authors.lastname: Lavebratt
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, and Department of Adult Psychiatry, PRIMA Barn och Vuxenpsykiatri AB, Stockholm (Dr Olsson); Department of Psychiatry, Tiohundra AB, Norrtälje (Drs Edman and Ösby and Ms Hukic); Department of Neurobiology, Care Sciences and Society, Centre of Family Medicine, Karolinska Institutet, Stockholm (Drs Edman and Ösby); Center for Molecular Medicine, Karolinska University Hospital, Stockholm (Drs Edman, Lavebratt, and Ösby); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm (Dr Bertilsson); Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Drs Hukic and Lavebratt); and Department of Cardiology, Danderyd University Hospital, Karolinska Institutet, Stockholm (Dr Eriksson), Sweden.
authors.forename: Sven V
authors.initials: SV
authors.lastname: Eriksson
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, and Department of Adult Psychiatry, PRIMA Barn och Vuxenpsykiatri AB, Stockholm (Dr Olsson); Department of Psychiatry, Tiohundra AB, Norrtälje (Drs Edman and Ösby and Ms Hukic); Department of Neurobiology, Care Sciences and Society, Centre of Family Medicine, Karolinska Institutet, Stockholm (Drs Edman and Ösby); Center for Molecular Medicine, Karolinska University Hospital, Stockholm (Drs Edman, Lavebratt, and Ösby); Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm (Dr Bertilsson); Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Drs Hukic and Lavebratt); and Department of Cardiology, Danderyd University Hospital, Karolinska Institutet, Stockholm (Dr Eriksson), Sweden.
authors.forename: Urban
authors.initials: U
authors.lastname: Ösby