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Clinical Pharmacogenomics Of Human Cyp2d6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Clozapine is metabolized by CYP1A2, 3A4, 2C9, 2C19, and 2D6 (Olesen and Linnet 2001). It can be expected that CYP2D6 phenotype status would not significantly change the kinetics of clozapine. In vivo studies have supported a role for CYP1A2 (Bertilsson et al. 1994), but no association has been found for metabolizer status with regard to debrisoquine (CYP2D6) or S-mephenytoin (CYP2C19) (Dahl et al. 1994a). Clozapine-induced agranulocytosis is not associated with polymorphisms of CYP2D6 and myeloperoxidase (Dettling et al. 2000). In addition, clozapine and N-desmethylclozapine concentration ratios are not related to the CYP2D6 genotype in patients (Melkersson et al. 2007).
The role of UDP-glycosyltransferases in xenobioticresistance
Published in Drug Metabolism Reviews, 2022
Diana Dimunová, Petra Matoušková, Radka Podlipná, Iva Boušová, Lenka Skálová
Several antipsychotic drugs also serve as substrates for UGTs, e.g. olanzapine, which is conjugated by UGT1A4. In the treatment of schizophrenia and bipolar disorder, a fixed-dose combination medication containing olanzapine and the opioid antagonist samidorphan is used. Coadministration of olanzapine/samidorphan with rifampin, a known CYP3A4 and UGT inducer, decreased the Cmax and AUC of olanzapine and samidorphan in healthy volunteers. The decrease in systemic exposure to olanzapine was likely due to both UGT1A4- and CYP3A4-mediated increases in olanzapine clearance (Sun et al. 2019). Clozapine is an antipsychotic drug approved for the treatment of refractory schizophrenia which is metabolized to an active N-desmethylclozapine metabolite. Glucuronidation is an important way of clozapine metabolism, with UGT1A4 being the only active isoform toward N-desmethylclozapine (Erickson-Ridout et al. 2012). In patients with schizoaffective disorders, a combination of clozapine with valproate is often used, although increasing the dose of valproate reduces levels of N-desmethylclozapine. The suggested mechanism of this reduction is the presystemic induction of UGTs or efflux transporters (Smith et al. 2019).
Pharmacotherapy of schizophrenia: immunological aspects and potential role of immunotherapy
Published in Expert Review of Neurotherapeutics, 2021
Prerna Chauhan, Gurjit Kaur, Rajendra Prasad, Harmanjit Singh
Several in vitro studies examined the effect of clozapine on cytokine production in cell culture assays. One of these studies reported inhibitory effect of clozapine metabolite (N-desmethylclozapine) on TNF and IL-2 but stimulatory effect on IL-17 [77]. Another in vitro study reported that clozapine (10−4-10−6 M) increased the stimulated and unstimulated IL-1 RA production, suggesting their immunosuppressive effects [78]. On the contrary, study conducted by Rudolf et al., showed that IL-2 levels were not influenced by clozapine treatment [79]. Earlier clinical study reported that long-term clozapine treatment (6 weeks) significantly increased plasma sIL-2 R levels in schizophrenics [80]. However, another study showed normalized TNF-a levels following 10-week clozapine treatment in 17 chronic patients of schizophrenia [81]. Study of 18 chronic schizophrenia patients reported that treatment with clozapine increased the expression of dopamine receptor (DRD3) on CD4+ cells; however, no significant change was observed in DRD4 expression. Findings from this study suggest potential of clozapine to disrupt peripheral immune cell and dopaminergic signaling [44].
The clozapine to norclozapine ratio: a narrative review of the clinical utility to minimize metabolic risk and enhance clozapine efficacy
Published in Expert Opinion on Drug Safety, 2020
Kenya A. Costa-Dookhan, Sri Mahavir Agarwal, Araba Chintoh, Veronica N. Tran, Nicolette Stogios, Bjørn H. Ebdrup, Sanjeev Sockalingam, Tarek K. Rajji, Gary J. Remington, Dan Siskind, Margaret K. Hahn
This narrative review follows the Joanna Briggs Institute (JBI) guidelines for research syntheses [50]. MEDLINE, Google Scholar, and PsychINFO databases were searched for articles containing the following MESH terms: treatment-resistant schizophrenia [AND] plasma clozapine [AND] plasma N-desmethylclozapine [OR] plasma NDMC [OR] plasma norclozapine [AND] ratio [AND] cardiometabolic outcomes [OR] metabolic side effects [OR] cognitive functioning [OR] psychopathology [OR] positive [AND] negative symptoms. Psychopathological treatment outcomes were inclusive of all schizophrenia symptom domains measured by the following validated schizophrenia-symptom rating scales: Scale for Assessment of Positive Symptoms (SAPS), Scale for Assessment of Negative Symptoms (SANS), and Brief Psychiatric Rating Scale (BPRS). Cognitive functioning outcomes included seven overall dimensions of schizophrenia-related cognitive impairment [51] and cognitive assessments included all reliable and validated scales to assess cognition in schizophrenia. Metabolic outcomes were reported from physical and hematological assessments. Outcomes include weight, body mass index (BMI), hyperlipidemia, hyperglycemia, and insulin resistance.