Optimization of Clonazepam Therapy Adjusted to Patient's CYP3A Status and NAT2 Genotype.
Article Details
- CitationCopy to clipboard
Toth K, Csukly G, Sirok D, Belic A, Kiss A, Hafra E, Deri M, Menus A, Bitter I, Monostory K
Optimization of Clonazepam Therapy Adjusted to Patient's CYP3A Status and NAT2 Genotype.
Int J Neuropsychopharmacol. 2016 Dec 30;19(12). pii: pyw083. doi: 10.1093/ijnp/pyw083. Print 2016 Dec.
- PubMed ID
- 27639091 [ View in PubMed]
- 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 nongenetic factors. METHODS: Since the prominent role in clonazepam nitro-reduction and acetylation of 7-amino-clonazepam is assigned to CYP3A and N-acetyl transferase 2 enzymes, respectively, the association between the patients' CYP3A status (CYP3A5 genotype, CYP3A4 expression) or N-acetyl transferase 2 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 bodyweight (1263.5+/-482.9 and 558.5+/-202.4ng/mL per mg/kg bodyweight in low and normal expressers, respectively, P<.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+/-0.024mg/kg bodyweight, P<.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 slower N-acetylation than all the others. CONCLUSION: Prospective assaying of CYP3A4 expression and N-acetyl transferase 2 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.
