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

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

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

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

Phenoconversion of CYP2D6 by inhibitors modifies aripiprazole exposure

The efficacy of aripiprazole therapy and the risk of adverse reactions are influenced by substantial inter-individual variability in aripiprazole metabolizing capacity. In vitro studies assigned the potential role in aripiprazole metabolism to CYP2D6 and CYP3A enzymes; therefore, the association between the steady-state aripiprazole plasma concentrations and patients' CYP2D6 and CYP3A statuses (CYP2D6, CYP3A4, and CYP3A5 genotypes, and CYP3A4 expression) and/or co-medication with CYP function modifying medications has been investigated in 93 psychiatric patients on stable aripiprazole therapy. The patients' CYP2D6 genotype had a major effect on aripiprazole plasma concentrations, whereas contribution of CYP3A genotypes and CYP3A4 expression to aripiprazole clearance were considered to be minor or negligible. The role of CYP3A4 expression in aripiprazole metabolism did not predominate even in the patients with nonfunctional CYP2D6 alleles. Furthermore, dehydroaripiprazole exposure was also CYP2D6 genotype-dependent. Dehydroaripiprazole concentrations were comparable with aripiprazole levels in patients with functional CYP2D6 alleles, and 35% or 22% of aripiprazole concentrations in patients with one or two non-functional CYP2D6 alleles, respectively. The concomitant intake of CYP2D6 inhibitors, risperidone, metoprolol, or propranolol was found to increase aripiprazole concentrations in patients with at least one wild-type CYP2D6*1 allele. Risperidone and 9-hydroxy-risperidone inhibited both dehydrogenation and hydroxylation of aripiprazole, whereas metoprolol and propranolol blocked merely the formation of the active dehydroaripiprazole metabolite, switching towards the inactivation pathways. Patients' CYP2D6 genotype and co-medication with CYP2D6 inhibitors can be considered to be the major determinants of aripiprazole pharmacokinetics. Taking into account CYP2D6 genotype and co-medication with CYP2D6 inhibitors may improve the outcomes of aripiprazole therapy