title: Sex differences in plasma clozapine and norclozapine concentrations in clinical practice and in relation to body mass index and plasma glucose concentrations: a retrospective survey.
abstract: BACKGROUND
  Clozapine is widely prescribed and, although effective, can cause weight gain and dysglycemia. The dysmetabolic effects of clozapine are thought to be more prevalent in women with this gender on average attaining 17 % higher plasma clozapine concentrations than men.
  
  
  METHODS
  We investigated the relationship between dose, body mass index (BMI), plasma glucose concentration, and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in 100 individuals with a severe enduring mental illness.
  
  
  RESULTS
  Mean (10th/90th percentile) plasma clozapine concentrations were higher for women [0.49 (0.27-0.79) mg/L] compared with men [0.44 (0.26-0.70) mg/L] (F = 2.2; p = 0.035). There was no significant gender difference in the prescribed clozapine dose. BMI was significantly higher in women [mean (95 % CI) = 34.5 (26.0-45.3)] for females compared with 32.5 (25.2-41.0) for males. Overall, BMI increased by 0.7 kg/m(2) over a mean follow-up period of 210 days. A lower proportion, 41 % of women had a fasting blood glucose ≤6.0 mmol/L (<6.0 mmol/L is defined by the International Diabetes Federation as normal glucose handling), compared with 88 % of men (χ (2) = 18.6, p < 0.0001).
  
  
  CONCLUSIONS
  We have shown that mean BMI and blood glucose concentrations are higher in women prescribed clozapine than in men. Women also tended to attain higher plasma clozapine concentrations than men. The higher BMI and blood glucose in women may relate to higher tissue exposure to clozapine, as a consequence of sex differences in drug metabolism.
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK ; The George Institute for Global Health, Nuffield Department of Population Health, Oxford Martin School, University of Oxford, Oxford, UK.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Anderson
authors.affiliation: Department of Blood Sciences, Walsall Manor Hospital, Walsall, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Livingston
authors.affiliation: Toxicology Unit, Department of Clinical Biochemistry, King's College Hospital NHS Foundation Trust, London, UK.
authors.forename: Lewis
authors.initials: L
authors.lastname: Couchman
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Smith
authors.affiliation: Intensive Psychiatric Care Unit, Gartnavel Royal Hospital, Glasgow, UK.
authors.forename: Moira
authors.initials: M
authors.lastname: Connolly
authors.affiliation: Pharmacy, Prestwich Hospital, Prestwich, Greater Manchester, UK.
authors.forename: Joan
authors.initials: J
authors.lastname: Miller
authors.affiliation: Toxicology Unit, Department of Clinical Biochemistry, King's College Hospital NHS Foundation Trust, London, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Flanagan
authors.affiliation: Department of Medicine, Leighton Hospital, Crewe, CW1 4QJ UK ; School of Medicine and Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
authors.forename: A H
authors.initials: AH
authors.lastname: Heald
keywords: BMI; Clozapine; Gender; Glucose