Eric Olsson1, Gunnar Edman1, Leif Bertilsson1, Dzana Sudic Hukic1, Catharina Lavebratt1, Sven V Eriksson1, Urban Ösby1. 1. 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.
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. METHOD: 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.
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. METHOD: There were 113 patients on clozapine treatment recruited from psychosisoutpatient 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.
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