title: Influence of CYP2C19 polymorphism and concomitant antiepileptic drugs on serum clobazam and N-desmethyl clobazam concentrations in patients with epilepsy.
abstract: OBJECTIVE
  The aims of this study were to identify the factors influencing the metabolism of clobazam (CLB) and its active metabolite [N-desmethyl clobazam (NCLB)] and to evaluate the NCLB concentration as an indicator for CYP2C19 polymorphism in epileptic patients.
  
  
  METHODS
  A total of 302 serum samples from 238 Japanese patients were evaluated. The ratios of the serum CLB and NCLB concentrations to the CLB dose (CD ratios) were calculated and compared with CYP2C19 phenotypes.
  
  
  RESULTS
  The mean CD ratio of NCLB in extensive metabolizers (EM: *1/*1), intermediate metabolizers (IM: *1/*2 or *1/*3), and poor metabolizers (PM: *2/*2, *3/*3, or *2/*3) was 3.1, 4.9, and 21.6 (μg/mL)/(mg/kg), respectively. In the EM and IM groups, the concomitant use of hepatic enzyme inducers (phenytoin and carbamazepine) reduced the CD ratio of CLB and increased that of NCLB. In the PM group, these inducers also decreased the CD ratio for CLB but did not elevate the CD ratio for NCLB. Using multiple regression analysis, body weight showed a positive correlation with an increased CD ratio for NCLB. The concomitant use of zonisamide and stiripentol also elevated the CD ratio for NCLB in the EM and IM groups, but that of the PM group was almost unchanged. When the cut-off value of the CD ratio for NCLB was set as 10.0 (μg/mL)/(mg/kg) for predicting the CYP2C19 PM status, the sensitivity and specificity were 94.4% and 95.7%, respectively.
  
  
  CONCLUSIONS
  The interaction between NCLB and other antiepileptic drugs showed marked differences among CYP2C19 phenotypes. Measurement of the serum NCLB concentration is clinically useful for identifying the PM phenotype.
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Ulushiyama, Aoi-ku, Japan. yamamoty@szec.hosp.go.jp
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Katsumi
authors.initials: K
authors.lastname: Imai
authors.forename: Kou
authors.initials: K
authors.lastname: Miyakawa
authors.forename: Shigeko
authors.initials: S
authors.lastname: Nishimura
authors.forename: Risa
authors.initials: R
authors.lastname: Kasai
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.forename: Rumiko
authors.initials: R
authors.lastname: Takayama
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Mogami
authors.forename: Tokito
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Terada
authors.forename: Kazumi
authors.initials: K
authors.lastname: Matsuda
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kagawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People; D001569:Benzodiazepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000078306:Clobazam; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D001569:Benzodiazepines; D000078306:Clobazam; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C024581:N-desmethylclobazam