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Optimization of clonazepam therapy adjusted to patient's CYP3A-status and NAT2 genotype

Tóth, Katalin and Csukly, Gábor and Sirok, Dávid and Belic, Ales and Háfra, Edit and Déri, Máté Tamás and Menus, Ádám and Bitter, István and Monostory, Katalin (2016) Optimization of clonazepam therapy adjusted to patient's CYP3A-status and NAT2 genotype. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 19 (12). pp. 1-9. ISSN 1461-1457

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Abstract

BACKGROUND: The shortcomings of clonazepam therapy include tolerance, withdrawal symptoms and adverse effects, such as drowsiness, dizziness and confusion leading to increased risk of falls. Inter-individual variability in the incidence of adverse events in patients partly originates from the differences in clonazepam metabolism due to genetic and non-genetic factors. METHODS: Since the prominent role in clonazepam nitro-reduction and in acetylation of 7-amino-clonazepam is assigned to CYP3A and NAT2 enzymes, respectively, the association between the patients' CYP3A-status (CYP3A5 genotype, CYP3A4 expression) or NAT2 acetylator phenotype and clonazepam metabolism (plasma concentrations of clonazepam and 7-amino-clonazepam) was evaluated in 98 psychiatric patients suffering from schizophrenia or bipolar disorders. RESULTS: The patients' CYP3A4 expression was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and the bodyweight (1263.5+/-482.9 and 558.5+/-202.4 ng/ml per mg/kg bw in low and normal expressers, respectively, P<0.0001). Consequently, the dose-requirement for the therapeutic concentration of clonazepam was substantially lower in low CYP3A4 expresser patients than in normal expressers (0.029+/-0.011 vs 0.058+/-0.024 mg/kg bw, P<0.0001). Furthermore, significantly higher (about 2-fold) plasma concentration ratio of 7-amino-clonazepam and clonazepam was observed in the patients displaying normal CYP3A4 expression and slow N-acetylation than all the others. CONCLUSION: Prospective assaying of CYP3A4 expression and NAT2 acetylator phenotype can better identify the patients with higher risk of adverse reactions and can facilitate the improvement of personalized clonazepam therapy and withdrawal regimen.

Item Type: Article
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry / idegkórtan, neurológia, pszichiátria
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 25 Jan 2017 14:49
Last Modified: 10 Jan 2018 01:48
URI: http://real.mtak.hu/id/eprint/46236

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