title: Optimization of Clonazepam Therapy Adjusted to Patient's CYP3A Status and NAT2 Genotype.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary (Ms Tóth, Mr Sirok, Mr Kiss, Ms Háfra, Mr Déri, and Dr Monostory); Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary (Drs Csukly, Menus, and Bitter); Toxi-Coop Toxicological Research Center, Budapest, Hungary (Mr Sirok); University of Ljubljana, Ljubljana, Slovenia (Dr Belic).|K.T. and G.C. contributed equally to the content of the work.
authors.forename: Katalin
authors.initials: K
authors.lastname: Tóth
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary (Ms Tóth, Mr Sirok, Mr Kiss, Ms Háfra, Mr Déri, and Dr Monostory); Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary (Drs Csukly, Menus, and Bitter); Toxi-Coop Toxicological Research Center, Budapest, Hungary (Mr Sirok); University of Ljubljana, Ljubljana, Slovenia (Dr Belic).|K.T. and G.C. contributed equally to the content of the work.
authors.forename: Gábor
authors.initials: G
authors.lastname: Csukly
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary (Ms Tóth, Mr Sirok, Mr Kiss, Ms Háfra, Mr Déri, and Dr Monostory); Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary (Drs Csukly, Menus, and Bitter); Toxi-Coop Toxicological Research Center, Budapest, Hungary (Mr Sirok); University of Ljubljana, Ljubljana, Slovenia (Dr Belic).|K.T. and G.C. contributed equally to the content of the work.
authors.forename: Dávid
authors.initials: D
authors.lastname: Sirok
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary (Ms Tóth, Mr Sirok, Mr Kiss, Ms Háfra, Mr Déri, and Dr Monostory); Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary (Drs Csukly, Menus, and Bitter); Toxi-Coop Toxicological Research Center, Budapest, Hungary (Mr Sirok); University of Ljubljana, Ljubljana, Slovenia (Dr Belic).|K.T. and G.C. contributed equally to the content of the work.
authors.forename: Ales
authors.initials: A
authors.lastname: Belic
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary (Ms Tóth, Mr Sirok, Mr Kiss, Ms Háfra, Mr Déri, and Dr Monostory); Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary (Drs Csukly, Menus, and Bitter); Toxi-Coop Toxicological Research Center, Budapest, Hungary (Mr Sirok); University of Ljubljana, Ljubljana, Slovenia (Dr Belic).|K.T. and G.C. contributed equally to the content of the work.
authors.forename: Ádám
authors.initials: Á
authors.lastname: Kiss
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary (Ms Tóth, Mr Sirok, Mr Kiss, Ms Háfra, Mr Déri, and Dr Monostory); Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary (Drs Csukly, Menus, and Bitter); Toxi-Coop Toxicological Research Center, Budapest, Hungary (Mr Sirok); University of Ljubljana, Ljubljana, Slovenia (Dr Belic).|K.T. and G.C. contributed equally to the content of the work.
authors.forename: Edit
authors.initials: E
authors.lastname: Háfra
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary (Ms Tóth, Mr Sirok, Mr Kiss, Ms Háfra, Mr Déri, and Dr Monostory); Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary (Drs Csukly, Menus, and Bitter); Toxi-Coop Toxicological Research Center, Budapest, Hungary (Mr Sirok); University of Ljubljana, Ljubljana, Slovenia (Dr Belic).|K.T. and G.C. contributed equally to the content of the work.
authors.forename: Máté
authors.initials: M
authors.lastname: Déri
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary (Ms Tóth, Mr Sirok, Mr Kiss, Ms Háfra, Mr Déri, and Dr Monostory); Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary (Drs Csukly, Menus, and Bitter); Toxi-Coop Toxicological Research Center, Budapest, Hungary (Mr Sirok); University of Ljubljana, Ljubljana, Slovenia (Dr Belic).|K.T. and G.C. contributed equally to the content of the work.
authors.forename: Ádám
authors.initials: Á
authors.lastname: Menus
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary (Ms Tóth, Mr Sirok, Mr Kiss, Ms Háfra, Mr Déri, and Dr Monostory); Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary (Drs Csukly, Menus, and Bitter); Toxi-Coop Toxicological Research Center, Budapest, Hungary (Mr Sirok); University of Ljubljana, Ljubljana, Slovenia (Dr Belic).|K.T. and G.C. contributed equally to the content of the work.
authors.forename: István
authors.initials: I
authors.lastname: Bitter
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary (Ms Tóth, Mr Sirok, Mr Kiss, Ms Háfra, Mr Déri, and Dr Monostory); Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary (Drs Csukly, Menus, and Bitter); Toxi-Coop Toxicological Research Center, Budapest, Hungary (Mr Sirok); University of Ljubljana, Ljubljana, Slovenia (Dr Belic). monostory.katalin@ttk.mta.hu.|K.T. and G.C. contributed equally to the content of the work. monostory.katalin@ttk.mta.hu.
authors.forename: Katalin
authors.initials: K
authors.lastname: Monostory
mesh_terms: D000107:Acetylation; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D001711:Biotransformation; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D002998:Clonazepam / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D012559:Schizophrenia / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D012565:Schizophrenic Psychology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D002998:Clonazepam; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human
keywords: 
  NAT2 genotype; CYP3A4 expression; personalized clonazepam therapy; plasma concentration of 7-amino-clonazepam