Abstract
Clozapine is effective in treatment-resistant schizophrenia; however, adverse effects often result in discontinuation of clozapine therapy. Many of the side-effects are associated with pharmacokinetic variations; therefore, the expression of major clozapine-metabolizing enzymes (CYP1A2, CYP3A4) in patients may predict development of adverse effects. In patients with schizophrenia (N = 96), development of clozapine concentration-dependent metabolic side-effects was found to be associated with pharmacokinetic variability related to CYP3A4 but not to CYP1A2 expression. In low CYP3A4 expressers, significant correlation was detected between fasting glucose level and clozapine concentration; moreover, the incidence of abnormal glucose level was associated with exaggerated clozapine concentrations (> 600 ng/ml). In low CYP3A4 expressers, exaggerated concentrations were more frequently observed than in normal/high expressers. Moderate/high risk obesity (BMI ≥ 35) more frequently occurred in low CYP3A4 expresser patients than in normal/high expressers. In patients with normal/high CYP3A4 expression and consequently with extensive clozapine-metabolizing capacity, norclozapine/clozapine ratio correlated with fasting glucose levels, triglyceride concentrations and BMI. Low CYP3A4 expression often resulting in exaggerated clozapine concentrations was considered to be as an important risk factor for some concentration-dependent adverse effects as normal/high CYP3A4 expression evoking high norclozapine/clozapine ratios. CYP3A4-status can identify patients with increased risk for metabolic side-effects and prevent their development by careful therapeutic strategy.
Highlights
Clozapine is effective in treatment-resistant schizophrenia; adverse effects often result in discontinuation of clozapine therapy
Clozapine is metabolized in the liver by various cytochrome P450 enzymes (CYP1A2, CYP3A4, CYP2C19, CYP2D6) and flavin-containing monooxygenase 321,22; CYP1A2 and CYP3A4 enzymes seem to be primarily responsible for the main metabolic pathways, forming two major metabolites, the pharmacologically active norclozapine and the inactive clozapine N-oxide[23,24]
Strong association was observed between norclozapine formation and CYP3A4 expression [0.56 ± 0.17 vs 0.98 ± 0.62, Kruskal–Wallis ChiSq = 22.9, N = 96, P < 0.0001] (Fig. 2A), and further contribution of CYP1A2 to norclozapine production was demonstrated [0.86 ± 0.55 vs 1.17 ± 0.70, Kruskal–Wallis ChiSq = 11.5, N = 73, P = 0.0007] (Fig. 2B)
Summary
Clozapine is effective in treatment-resistant schizophrenia; adverse effects often result in discontinuation of clozapine therapy. Many of the side-effects are associated with pharmacokinetic variations; the expression of major clozapine-metabolizing enzymes (CYP1A2, CYP3A4) in patients may predict development of adverse effects. In patients with schizophrenia (N = 96), development of clozapine concentration-dependent metabolic side-effects was found to be associated with pharmacokinetic variability related to CYP3A4 but not to CYP1A2 expression. Moderate/high risk obesity (BMI ≥ 35) more frequently occurred in low CYP3A4 expresser patients than in normal/high expressers. In patients with normal/high CYP3A4 expression and with extensive clozapine-metabolizing capacity, norclozapine/clozapine ratio correlated with fasting glucose levels, triglyceride concentrations and BMI. Low CYP3A4 expression often resulting in exaggerated clozapine concentrations was considered to be as an important risk factor for some concentration-dependent adverse effects as normal/high CYP3A4 expression evoking high norclozapine/clozapine ratios. Both clozapine and norclozapine have antagonist effect on 5-HT2C receptors, which likely contributes to clozapine-induced weight g ain[11]
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