Optimization of Clonazepam Therapy Adjusted to Patient's CYP3A Status and NAT2 Genotype.

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.

SUBMITTER: Toth K 

PROVIDER: S-EPMC5203763 | biostudies-literature |

REPOSITORIES: biostudies-literature